Substituted [1,2,4]triazolo[1,5-A]pyrimidin-7-yl compounds as PDE2 inhibitors

ABSTRACT

The invention provides a chemical entity of Formula (I) wherein R 1 , R 2 , X, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods as disclosed herein, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by PDE2 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, and dermatological disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application is a U.S. National Phase ofInternational Application No. PCT/US2015/027102, filed on Apr. 22, 2015and published on Oct. 29, 2015 as WO 2015/164508, which claims thebenefit of U.S. Provisional Application 61/983,387, filed on Apr. 23,2014, which is incorporated herein by reference in its entirety.

BACKGROUND

Field

The present invention relates to certain substituted[1,2,4]triazolo[1,5-a]pyrimidinyl compounds and derivatives of suchcompounds; pharmaceutical compositions containing them; methods ofmaking them; and their use in various methods, including the inhibitionof PDE2, and the treatment of one or more disorders, includingneurological disorders, psychotic disorders, dementia, and otherconditions and diseases involving PDE2.

Description of the Related Technology

The mammalian phosphodiesterases (PDEs) are a group of closely relatedenzymes divided into 11 families (PDE1-11) based on substratespecificity, inhibitor sensitivity and more recently, on sequencehomology. The 11 families are coded by 21 genes, providing several ofthe families with multipR^(a) members. All mammalian PDEs share aconserved catalytic domain located in the COOH-terminal portion of theprotein. In GAF-containing PDEs, one or both GAFs can providedimerization contacts. In addition, one of the GAFs in each of theseproteins provides for allosteric cGMP binding (PDE2, PDE5, PDE6, PDE11),allosteric cAMP binding (PDE10), and regulation of catalytic sitefunctions (PDE2, PDE5, PDE6). The other families of PDEs have uniquecomplements of various subdomains (UCR, NHR, PAS, membrane association)that contribute to regulation of activity. PDEs 1, 2, 3, and 4 areexpressed in many tissues, whereas others are more restricted. Thehomology between families, suggests that it may be possible to developselective inhibitors for each of these subtypes. Numerous studies havehighlighted a role for PDEs generally, in modulating intracellularsignaling pathways that regulate many physiological processes, includingthose underling neural plasticity, cognition, and memory (Menniti etal., 2006, Nat Rev Drug Discov. 5, 660-670). In particular, PDEs play animportant role in intracellular signal transduction pathways involvingthe second messengers, cAMP and cGMP (phosphodiesterase 2 and 10inactivate both cAMP and cGMP. These cyclic nucleotides function asubiquitous intracellular signaling molecules in all mammalian cells. PDEenzymes hydrolyze cAMP and cGMP by breaking phosphodiester bonds to formthe corresponding monophosphates (Bender and Beavo, Pharmacol. Rev.,2006, 58(3), 488-520). PDE activities are modulated in coordination withadenylyl cyclase (AC) and guanylyl cyclase (GC) activities throughdirect effectors and feedback pathways, thereby maintaining cAMP andcGMP levels within optimum ranges for responsiveness to signals. Theability of extracellular signals to modulate the intracellularconcentration of cyclic nucleotides allows cells to respond to externalstimuli across the boundary of the cell membrane.

The cyclic nucleotide signaling cascades have been adapted to respond toa host of transduction systems including G-protein coupled receptors(GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotidestransmit their signal in the cell through a variant of tertiaryelements. The best described of these are cAMP dependent protein kinase(PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclicnucleotide to each enzyme enables the phosphorylation of downstreamenzymes and proteins functioning as effectors or additional elements inthe signaling cascade. Of particular importance to memory formation iscAMP activation of PKA which phosphorylates cAMP responseelement-binding protein (CREB). pCREB is an activated transcriptionfactor, which binds to specific DNA loci and initiates transcription ofmultiple genes involved in neuronal plasticity. Both in vitro and invivo studies have associated alterations in cyclic nucleotideconcentrations with biochemical and physiological process linked tocognitive function (Kelly and Brandon, Progress in Brain Research, 2009,179, 67-73; Schmidt, Current Topics in Medicinal Chemistry, 2010, 10,222-230). Signal intensity and the levels of coincident activity at asynapse are established variables that can result in potentiation oftransmission at a particular synapse. Long term potentiation (LTP) isthe best described of these processes and is known to be modulated byboth the cAMP and cGMP signaling cascades.

PDE2 inhibitors have been shown to enhance long term potentiation ofsynaptic transmission and to improve memory acquisition andconsolidation in the object recognition and in the social recognitiontests in rats. PDE2 inhibitors have also been shown to display activityin forced swim test and light/dark box models; and to showanxiolytic-like effects in elevated plus-maze, hole-board and open-fieldtests; and to prevent stress-induced changes in apoptosis and behaviour(Boess et al., Neuropharmacology, 2004, 47 (7) 1081-92; Masood et al. J.Pharmacol. Exp. Ther. 2009, 331, 690-699). Additionally, it is reportedthat a selective PDE2 inhibitor is efficacious in the novel objectrecognition test, the social recognition test and the T-maze, an animalmodel of working memory (Rutten et al., Eur. J. Neurosci., 2007,558(1-3), 107-112). Moreover, PDE2 inhibitors appear beneficial inreducing oxidative stress-induced anxiety, supporting their use intreating anxiety in psychiatric disorders and neurodegenerativedisorders that oxidative stress, such as Alzheimer's disease,Parkinson's disease and multiple sclerosis. (Masood et al., J.Pharmacol. Exp. Ther., 2008, 326, 369-379).

Such observations highlight the interest in inhibiting PDEs, includingPDE2, as a therapeutic target for numerous disorders and in cognitiveenhancement. Various small-molecule PDE2 enzyme inhibitors have beenreported e.g., substituted triazolopyrazines (H. Lundbeck A/S, Intl.Pat. Appl. Publ. WO2013/034755, Mar. 14, 2013 and Intl. Pat. Appl. Publ.WO2013/034758, Mar. 14, 2013), pyridine compounds (H. Lundbeck A/S,Intl. Pat. Appl. Publ. WO2013/034761, Mar. 14, 2013),1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalines (JanssenPharmaceutica NV, Intl. Pat. Appl. Publ. WO2013/000924, Jan. 3, 2013),pyrazolopyrimidines (Pfizer Inc., Intl. Pat. Appl. Publ. WO2012/168817,Dec. 13, 2012), imidazo[5,1-f][1,2,4]triazines (Pfizer Inc., U.S. Pat.No. 8,598,155, Aug. 23, 2012), (1,2,4)triazolo[4,3-a]quinoxalines(Boehringer Ingelheim International GmbH, Intl. Pat. Appl. Publ.WO2012/104293, Aug. 9, 2012), quinolinones (Merck Sharp & Dohme Corp.,Intl. Pat. Appl. Publ. WO2011/011312, Jan. 27, 2011),imidazo[5,1-c][1,2,4]benzotriazines (Biotie Therapies GmbH, Intl. Pat.Appl. Publ. WO2010/054260, May 14, 2010), triazines (Biotie TherapiesGmbH, Intl. Pat. Appl. Publ. WO2010/054253, May 14, 2010),triazolophthalazines (Altana Pharma AG, U.S. Pat. No. 8,106,047, Jul.13, 2006; U.S. Pat. No. 7,671,050, Jul. 13, 2006; U.S. Pat. No.7,851,472, Mar. 9, 2006), benzo[1,4]diazepin-2-ones (Neuro3d, U.S. Pat.No. 7,410,963, Jun. 29, 2005), oxindoles (Pfizer Products Inc., Intl.Pat. Appl. Publ. WO2005/041957, May 12, 2005), and imidazotriazinones(Bayer AG, U.S. Pat. No. 6,573,263, Jun. 27, 2002 and EP Pat. 1,363,912,Sep. 5, 2002).

However, there remains a need for potent PDE2 inhibitors with desirablepharmaceutical properties, such as potency, exposure, selectivity, andside effect profile. The present invention addresses these and otherneeds in the art by disclosing substituted[1,2,4]triazolo[1,5-a]pyrimidin-7-yl compounds as potent andwell-tolerated PDE2 inhibitors.

SUMMARY

Some embodiments provide a chemical entity of Formula (I):

wherein

X is —CH₂— or —O—;

Y is —CH₂— or —CF₂—;

Z is —CH₂— or —C(═O)—;

R¹ is a member selected from the group consisting of:

-   -   (a) phenyl unsubstituted or substituted with one, two, three        four or five R^(a) members;        -   where R^(a) is each independently selected from the group            consisting of: —H, -halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl,            —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —CN, —N(C₁₋₆alkyl)₂, —SF₅,            —C₃₋₆cycloalkyl, -pyrrolidine, -morpholine, -piperidine,            -pyrazole, -furan, -imidazole, -thiophene, -thiazole,            -pyridine, and -phenyl, wherein phenyl is unsubstituted or            substituted with one, two, three, four or five R^(b)            members;        -   where R^(b) is each independently selected from the group            consisting of: —H, —Cl and —F; or optionally two adjacent            R^(a) members come together to form a ring, each optionally            unsubstituted or substituted with one or more members            independently selected from: —H, -halo, —C₁₋₆alkyl or            —C₁₋₆alkoxy;    -   (b) monocyclic or bicyclic heteroaromatic ring each        unsubstituted or substituted with one, two, three or four R^(c)        members;        -   where R^(c) is each independently selected from the group            consisting of: —H, -halo, —C₁₋₆alkyl, —C₁₋₄haloalkyl,            —C₁₋₄alkoxy, —N(C₁₋₆alkyl)₂, —(C₁₋₆alkyl)cycloalkyl,            -cyclopropyl, -morpholine, -pyrrolidine, -4-chlorophenoxy,            and -phenyl optionally unsubstituted or substituted with            -halo, —C₁₋₆alkyl or —C₁₋₄alkoxy; and    -   (c) heterocycloalkyl ring optionally unsubstituted or        substituted with one or more —H, —F, or —OCH₃; and

R₂ is —C₁₋₆alkyl optionally substituted with five fluoro members.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I). In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

Some embodiments provide pharmaceutical compositions for treating adisease, disorder, or medical condition mediated by PDE2 activity,comprising an effective amount of at least one chemical entity selectedfrom compounds of Formula (1), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofFormula (I).

Pharmaceutical compositions according to the embodiments may furthercomprise one or more pharmaceutically acceptable excipients.

Some embodiments provide a method of treating a subject suffering fromor diagnosed with a disease, disorder, or medical condition mediated byPDE2 activity, comprising administering to the subject in need of suchtreatment an effective amount of at least one chemical entity selectedfrom compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I). Additional embodiments of methods of treatmentare set forth in the detailed description.

Chemical entities of compounds of Formula (I) are useful in wide rangeof methods. Isotopically-labeled compounds and prodrugs can be used inmetabolic and reaction kinetic studies, detection and imagingtechniques, and radioactive treatments. In certain embodiments, thechemical entities can be used to inhibit PDE2, in particular; to treat adisorder mediated by PDE2, in particular; to enhance neuronalplasticity; to treat neurological disorders, including neurodegenerativedisorders, cognitive disorders, and cognitive deficits associated withcentral nervous system (CNS) disorders; to facilitate neuroprotectionand neurorecovery; and to treat peripheral disorders, includinginfectious, hematological, cardiovascular, gastroenterological, anddermatological diseases. In certain embodiments, the chemical entitiesare also useful as augmenting agents to enhance the efficiency ofcognitive and motor training, including animal skill training protocols.The embodiments may be further directed to the general and specificembodiments defined, respectively, and by the independent and dependentclaims appended hereto, which are incorporated by reference herein.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

Abbreviations

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

TABLE 1 Abbreviation Definition ACN Acetonitrile AIBNAzobisisobutyronitrile BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBOC or tert-Butoxycarbonyl or Di-tert-butyl dicarbonate Boc₂O CELITE ®Diatomaceous earth CDI 1,1′-Carbonyldiimidazole m-CPBAmeta-Chloroperoxybenzoic acid DAST Diethylaminosulfur trifluoride DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCC Dicyclohexylcarbodiimide DCMDichloromethane Deoxo-Fluor ® Bis(2-methoxyethyl)aminosulfur trifluorideDIPEA N,N-Ethyl-diisopropylamine or N,N-Diisopropyl-ethyl amine DMAN,N-Dimethylacetamide DMAP 4-Dimethylamino pyridine DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide DPEphosBis[(2-diphenylphosphino)phenyl] ether dppf1,1′-Bis(diphenylphosphino)ferrocene EDCIN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EtOAc,Ethyl Acetate or EA EtOH Ethanol IPA Isopropyl alcohol HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) HOAc Acetic Acid or AcOH HOAT1-Hydroxy-7-azabenzotriazole HOBt 1-Hydroxybenzotriazole HPLCHigh-performance liquid chromatography LAH Lithium aluminum hydrideLiHMDS, Lithium bis(trimethylsilyl)amide LHMDS LDA Lithiumdiisopropylamide LCMS, Liquid chromatography-mass spectrometry LC/MSMeOH Methanol MsCl Methanesulfonyl chloride NBS N-Bromosuccinimide NMP1-Methyl-2-pyrrolidinone OTs p-Toluenesulfonic acid Pd/C Palladium onactivated carbon Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium (0)PdCl₂(dppf)-Cl₂ [1,′1′-Bis(diphenylphosphino)ferrocene]palla- adductdium(ll) dichloride dichloromethane adduct Pd(PPh₃)₄Palladium-tetrakis(triphenylphosphine) PE Petroleum ether PyBroPBromotripyrrolidinophosphonium hexafluorophosphate Selectfluor ®1-Chloromethyl-4-fluoro-1,4-diazoniabi- cyclo[2.2.2]octane S-Phos2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TEA, Triethylamine Et₃NTFA Trifluoroacetic acid THF Tetrahydrofuran TMEDATetramethylethylenediamine Xantphos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XtalFluor ®Diethylaminodifluorosulfinium tetrafluoroborate

Terms and Definitions

The use of subheadings such as “General,” “Chemistry,” “Compositions,”“Formulations,” etc., in this section, as well as in other sections ofthis application, are solely for convenience of reference and notintended to be limiting.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5-fold, or within2-fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity for which that could be obtained under the particularstoichiometric conditions. Concentrations that are given as percentagesrefer to mass ratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

Although items, elements or components of the invention may be describedor claimed in the singular, the plural is contemplated to be within thescope thereof, unless limitation to the singular is explicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended, as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known,” and terms of similar meaning should not be construed aslimiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or criterion technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to,” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. As will becomeapparent to one of ordinary skill in the art after reading thisdocument, the illustrated embodiments and their various alternatives maybe implemented without confinement to the illustrated examples.

Chemistry

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “-”), ethyl (Et), n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl,isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of theordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples. Alkyl groupsmay be optionally substituted with one or more substituents including,but not limited to, hydroxyl, alkoxy, thioalkoxy, amino, and aminoalkyl.

The term “alkenyl” refers to optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon double bond andincluding E and Z isomers of said alkenyl moiety. Examples of alkenylradicals include ethenyl, propenyl, butenyl, 1,4-butadienyl,cyclopentenyl, cyclohexenyl and the like.

The term “alkynyl” refers to an optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon triple bond andincludes straight and branched chain alkynyl groups. Examples of alkynylradicals include ethynyl, propynyl, butynyl and the like.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain optionally substitutinghydrogens with halogens. Examples of haloalkyl groups include, but arenot limited to, —CF₃, —CHF, —CHF, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₂CF₃ and other groups that in light of the ordinaryskill in the art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “alkoxy” includes a straight chain or branched alkyl group withan oxygen atom linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl,” “thioalkyl,” and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

The term “haloalkoxy” refer to alkoxy groups optionally substitutinghydrogens with halogens. Examples of haloalkoxy groups include, but arenot limited to, —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂Cl, —OCH₂CF₂CF₃,—OCH(CH₃)CHF₂ and other groups that in light of the ordinary skill inthe art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “amino” refers to the —NH₂ group.

The term “alkylamino” refers to the —NRR′ group, where R and R′ areindependently selected from hydrogen (however, R and R′ cannot both behydrogen), alkyl, and aryl groups; or R and R′, taken together, can forma cyclic ring system. Examples of amino groups include, but are notlimited to, —NH(CH₃), —N(CH₃)₂, —NPhenyl(CH₃), —NHPhenyl,—N(CH₂CH₃)(CH₃), and the like.

The term “cyano” refers to the group —CN.

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon), having from 3 to 12 ring atoms per ring (carbon atoms in arylgroups are sp2 hybridized). Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “aryloxy” refers to a group having the formula, —O—R, wherein Ris an aryl group.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur), or N (nitrogen).

The term “substituted” means that the specified group or moiety bearsone or more substituents. Where the term “substituted” is used todescribe a structural system, unless specified otherwise, thesubstitution is meant to occur at any valency-allowed position on thesystem. The term “unsubstituted” means that the specified group bears nosubstituents.

Formulas

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The symbols - and

are used as meaning the same spacial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spacial arrangement in chemical structuresshown herein.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the undissociated formof the compound in a solvent; and R—COO-(sol) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO-upon dissociation in the medium being considered.

As used herein, the term “chemical entity” collectively refers to acompound, along with the derivatives of the compound, including salts,chelates, solvates, conformers, non-covalent complexes, metabolites, andprodrugs.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

In another example, an expression such as “exposing an entity to acompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a “zwitterionic” compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion +H₃NCH₂COO—. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,and ¹²⁵I, respectively.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R^(a), R^(b), R^(c), R^(d), X, Y, and Z and any other genericsubstituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R^(a), R^(c), R^(d), X, Y, and Z and any other generic substituentsymbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the second memberand B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is preferablynon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “metabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or salt thereof. Preferably, themetabolite is in an isolated form outside the body.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672;Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahland Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use:2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011). Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. A compound of Formula(I) may possess a sufficiently acidic group, a sufficiently basic group,or both types of functional groups, and accordingly react with a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21^(st) Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition.” For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease's cause, transmission, or expression) or notdirectly affecting the disease.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal). An“effective amount” also means an amount or dose of a compound orcomposition effective to modulate activity of PDE2 or an associatedsignaling pathway.

The “effective amount” will vary, depending on the compound, thedisease, the type of treatment desired, and its severity, and age,weight, etc.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing,” or “enhancement” is meant the ability topotentiate, increase, improve, or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to (or“compared to”) the normal long term memory formation of the animal orcontrols. As a result, long term memory acquisition is faster or betterretained. Enhancing performance of a cognitive task refers to theability to potentiate or improve performance of a specified cognitivetask by an animal relative to the normal performance of the cognitivetask by the animal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.”

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds

The present invention provides certain substituted[1,2,4]triazolo[1,5-a]pyrimidin-7-yl derivatives, which are useful, forexample, as inhibitors of PDE2 enzymatic activity. They are distinctfrom triazolo[1,5-a]pyrimidines (Vernalis Cambridge Limited, Int. Pat.App. WO2004/108136, Dec. 16, 2004), and methylsulfonyl compounds:Chemical Abstracts Service Registry Number 1381754-80-8, 1381750-79-3,1381747-28-9, 1381743-97-0, 1240215-31-9, 1240208-98-3, 1240201-99-3,1240195-90-7, 1240195-65-6, 1240181-24-1, 1240169-61-2, 1240166-99-7,1240166-22-6, 1240153-22-3, 1240128-18-0, 1240115-42-7, 1240102-95-7,1240093-87-1, 1240091-60-4, 1214610-92-0, 1214601-85-0, 1214591-56-6,1214486-88-0, 1214427-36-7, 958707-04-5, 958706-09-7, 958706-04-2,958618-14-9, 958596-27-5, 958586-25-9, 958585-88-1, 958583-82-9,958583-78-3.

In certain embodiments, of Formula (I), where X is —O—, and Y is —CH₂—.

In some embodiments, where X is —CH₂—, Y is —CF₂—.

In some embodiments, where X is —CH₂—, Y is —CH₂—.

In some embodiments Z is —CH₂—.

In some embodiments Z is —C(═O)—.

In some embodiments R² is —CH₃.

In some embodiments R¹ is phenyl unsubstituted or substituted with one,two, three, four, or five R^(a) members.

In some embodiments R^(a) is a member independently selected from thegroup consisting of: H, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆alkoxy,—C₁₋₆haloalkoxy, —CN, —N(C₁₋₆alkyl)₂, and —C₃₋₆cycloalkyl.

In some embodiments R^(a) is a member independently selected from: —H,—Cl, —Br, —F, —I, —C₁₋₄alkyl, —C₁₋₄haloalkyl, —C₁₋₄alkoxy,—C₁₋₄haloalkoxy, —CN, —N(CH₃)₂, or -cyclopropyl.

In some embodiments R^(a) is a member independently selected from:-pyrrolidine, -morpholine, -piperidine, -pyrazole, -furan, -imidazole,-thiophene, -thiazole, -pyridine, or phenyl substituted with one or more—H, —Cl or —F.

In some embodiments two adjacent R^(a) members optionally come togetherto form form a cyclopentyl, cyclohexyl, phenyl, pyridine, furan,tetrahydrofuran, tetrahydropyran, thiazole, thiophene, pyrrole, indole,1,4-dioane, or 1,3-dioxolane ring, each optionally unsubstituted orsubstituted with one or more members independently selected from —H,-halo, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In certain embodiments of Formula (I), R¹ is naphthalen-1-yl,naphthalen-2-yl, 6-methoxynaphthalen-2-yl, 1-methoxynaphthalen-2-yl,3-methoxynaphthalen-2-yl, 3-methoxynaphthalene-2-yl,6-fluoronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,5,6,7,8-tetrahydronaphthalene-2-yl, 2,3-dihydro-1H-inden-5-yl,2,3-dihydro-1H-inden-5-yl, 2H-1,3-benzodioxol-4-yl,2H-1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,2-difluoro-2H-1,3-benzodioxol-5-yl, 1-ethyl-1H-indole, indole,isoquinoline, 2,3-dihydro-1-benzofuran-5-yl,2,3-dihydro-1-benzofuran-6-yl, 3,4-dihydro-2H-1-benzopyran-6-yl,1-benzofuran, 1-benzofuran-5-yl, 1,3-benzothiazol-6-yl, or1-benzothiophen-5-yl.

In certain embodiments of Formula (I), R¹ is1-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl, 1-(2-chlorophenyl)-1H-pyrazol-3-yl,1-(2-fluorophenyl)-1H-pyrazol-3-yl, 1-(3-bromophenyl)-1H-pyrazol-3-yl,1-(3-fluorophenyl)-1H-pyrazol-3-yl,1-(4-chlorophenyl)-5-methyl-1H-pyrazol-3-yl,1-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl,1-(4-isopropylphenyl)-5-methyl-1H-pyrazol-3-yl, 1,3-benzothiazole,1,3-dimethyl-1H-pyrazol-5-yl, 1,5-dimethyl-1H-pyrazol-3-yl,1,5-dimethyl-1H-pyrazol-4-yl, 1,6-naphthyridin-2-yl, 1-benzofuran-2-yl,1-benzofuran-3-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl,1-ethyl-1H-pyrazol-5-yl, 1H-indol-3-yl, 1-isopropyl-1H-pyrazol-4-yl,1-methyl-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-indazol-3-yl,1-methyl-1H-indol-2-yl, 1-methyl-1H-indol-3-yl,1-methyl-3-(propan-2-yl)-1H-pyrazole, 1-methyl-3-phenyl-1H-pyrazol-5-yl,1-methyl-5-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-pyrazol-4-yl,1-phenyl-1H-pyrazol-4-yl, 2-(3-fluorophenyl)-1,3-thiazol-5-yl]methyl,2-(3-methoxyphenyl)-1,3-thiazol-5-yl, 2-(4-chlorophenoxy)pyridin-3-yl,2-(4-fluorophenyl)-1,3-thiazol-5-yl,2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl, 2,4-dimethylthiazol-5-yl,2,6-dimethylpyridin-3-yl, 2-bromo-1,3-thiazol-4-yl,2-bromo-1,3-thiazol-5-yl, 2-methoxypyridin-4-yl,2-methyl-1,3-thiazol-5-yl, 2-methyl-2H-indazol-3-yl,2-methyl-6-(trifluoromethyl)pyridin-3-yl,2-methylimidazo[1,2-a]pyridin-3-yl, 2-methylpyridin-3-yl,2-morpholinothiazol-5-yl, 2-phenyl-1,3-thiazol-5-yl,3,5-difluoropyridin-2-yl, 3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl,3,6-dimethylimidazo[2,1-b][1,3]thiazol-5-yl, 3-bromo-1,2-oxazol-5-yl,3-chloropyridin-4-yl, 3-cyclopropylisoxazol-5-yl, 3-fluoropyridin-4-yl,3-isopropyl-1-methyl-1H-pyrazol-5-yl, 3-methylpyridin-2-yl,3-methylpyridin-4-yl, 4-chloropyridin-2-yl, 4-methylpyridin-2-yl,5-bromo-4-methyl-1,3-thiazol-2-yl, 5-bromo-4-methylpyridin-2-yl,5-bromo-6-methylpyridin-2-yl, 5-bromopyridin-2-yl,5-bromopyrimidin-2-yl, 5-chloropyridin-2-yl, 5-chloropyridin-3-yl,5-cyclopropylisoxazol-3-yl, 5-cyclopropylisoxazol-4-yl,5-fluoro-1H-indol-3-yl, 5-fluoropyridin-3-yl, 5-methylpyridin-3-yl,6-methoxypyridin-3-yl, 6-methylpyridin-2-yl, 6-methylpyridin-3-yl,benzo[d]thiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyridin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl,N,N,4-trimethylthiazol-2-amine, N,N-dimethylthiazol-2-amine,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-2-yl, quinolin-3-yl,quinolin-4-yl, or quinoxalin-2-yl.

Some embodiments are given by compounds of Formula (I) where R¹ isindole, -benzothiophene, -pyrazole, -benzothiazole, -benzofuran,-oxazole, -indazole, -benzimidazole, -thiazole,-imidazo[2,1-b][1,3]thiazole, -imidazo[1,2-a]pyridine, -pyridine,-quinoxaline, -quinoline, -isoquinoline, -naphthyridine, or pyrimidine,each unsubstituted or substituted with one, two, three or four R^(c)members.

In certain embodiments of Formula (I), R¹ is -3,4-dihydro-2H-benzopyran,-2,3-dihydro-1,4-benzodioxine, -2,3-dihydro-1-benzofuran, or-1,2,3,4-tetrahydroisoquinoline, each optionally unsubstituted orsubstituted with one or more —H, —F, or —OCH₃.

In certain embodiments of Formula (I), R¹ is chroman-2-yl,6-fluorochroman-2-yl, chroman-3-yl, 7-methoxychroman-3-yl,2,3-dihydrobenzofuran-2-yl, (2,3-dihydrobenzo[b][1,4]dioxin-2-yl, or2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl.

Some embodiments are given by compounds of Formula (I) where R¹ isphenyl substituted with two or three R^(a) members independentlyselected from the group consisting of: —H, -halo, and —C₁₋₆haloalkyl.

Some embodiments are given by compounds of Formula (I) where Z is —C═O,—R¹ is 2,3-dihydro-1-benzo furan, 3,4-dihydro-2H-1-benzopyran,benzofuran, benzothiophene, naphthalene, quinoline, or phenyl, whereinphenyl is unsubstituted or substituted with two, three, or four R^(a)members, where R^(a) is a member independently selected from: —H, —Cl,—Br, —F, —I, —C₁₋₄alkyl, —C₁₋₄haloalkyl, —C₁₋₄alkoxy, —C₁₋₄haloalkoxy,—CN, —N(CH₃)₂, or -cyclopropyl.

Some embodiments are given by compounds of Formula (I) where Z is —CH₂,—R¹ is phenyl unsubstituted or substituted with two, three, or fourR^(a) members, where R^(a) is a member independently selected from: —H,—Cl, —Br, —F, —I, —C₁₋₄alkyl, —C₁₋₄haloalkyl, —C₁-4alkoxy, CN, —N(CH₃)₂,or -cyclopropyl.

In certain embodiments, a compound, or pharmaceutically acceptable saltthereof, of Formula (I) is selected from the group consisting ofExamples 1-566, as disclosed herein.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

Isotopically-Labeled Compounds

The invention also includes isotopically-labeled compounds, which areidentical to those recited in Formula I, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of carbon, chlorine, fluorine, hydrogen,iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and derivatives of such compounds,such as pharmaceutically acceptable salts and prodrugs) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentinvention are useful in drug and substrate tissue distribution andtarget occupancy assays. For example, isotopically labeled compounds areparticularly useful in SPECT (single photon emission computedtomography) and in PET (positron emission tomography), as discussedfurther herein.

Derivatives

The present invention also provides derivatives of a chemical entity ofFormula (I), which include, but are not limited to, any salt, solvate,conformer, or crystalline form/polymorph.

Salts

Accordingly, in one embodiment the invention includes pharmaceuticallyacceptable salts of the compounds represented by Formula (I), andmethods using such salts.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids (such as N-methyl-O-glucamine, lysine,choline, glycine, and arginine), ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, cyclic amines (such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine), and inorganic salts derived from sodium, calcium,potassium, magnesium, manganese, iron, copper, zinc, aluminum, andlithium.

Solvates

In other embodiments, the invention provides a solvate of a compound ofFormula (I), and the use of such solvates in methods of presentinvention. Certain compounds of Formula (I) or pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained assolvates. In some embodiments, the solvent is water and the solvates arehydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such asmethanol, methyl t-butyl ether, ethyl acetate, methyl acetate,(S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and thelike. Hydrates include compounds formed by an incorporation of one ormore water molecules.

Conformers and Crystalline Forms/Polymorphs

In other embodiments, the invention provides conformer and crystallineform of a compound of Formula (I), and the use of these derivatives inmethods of present invention. A conformer is a structure that is aconformational isomer. Conformational isomerism is the phenomenon ofmolecules with the same structural formula but different conformations(conformers) of atoms about a rotating bond.

A polymorph is a composition having the same chemical formula, but adifferent solid state or crystal structure. In certain embodiments ofthe invention, compounds of Formula (I) were obtained in crystallineform. In addition, certain crystalline forms of compounds of Formula (I)or pharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Prodrugs

The invention also relates to prodrugs of the compounds of Formula (I),and the use of such pharmaceutically acceptable prodrugs in methods ofthe present invention, particularly therapeutic methods. Exemplaryprodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₆alkyl, C₁₋₆cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130.

Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J. Med. Chem. 1996, 39, 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

Prodrugs may be determined using routine techniques known or availablein the art (e.g., Bundgard (ed.), 1985, Design of prodrugs, Elsevier;Krogsgaard-Larsen et al., (eds.), 1991, Design and Application ofProdrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

Compositions

In some embodiments compounds of Formula (I) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition of the invention comprises:(a) an effective amount of at least one active agent in accordance withthe invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, and other known additives to provide anelegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose, aspartame, or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac, or sugar, and the like. A syrup or elixirmay contain the active compound, sucrose or fructose as a sweeteningagent, methyl and propylparabens as preservatives, a dye and flavoringsuch as cherry or orange flavor. Of course, any material used inpreparing any unit dosage form should be pharmaceutically acceptable andsubstantially non-toxic in the amounts employed. In addition, the activecompound may be incorporated into sustained-release preparations anddevices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers, or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof formula I can be determined by comparing their in vitro activity, andin vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range from about0.01 to about 100 mg/kg, more specifically from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

Preferably, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, and more preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1 to 100mg of the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01 to 5.0 mg/kg/hr or byintermittent infusions containing about 0.4 to 15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four, or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

Methods and Uses

Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds and prodrugs of the present invention in:(i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) in radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Therapeutic Methods

Generally

Chemical entities of the present invention are useful in methods (or inthe manufacture of a medicament for use in such methods) of treating adisorder mediated by PDE2a by administering to a subject in need thereofan effective amount of a chemical entity of the present invention. Theyare also useful in methods (or in the manufacture of a medicament foruse in such methods) of enhancing cognitive or motor function mediatedby PDE2 by administering to a subject in need an effective amount of achemical entity of the present invention.

In one embodiment the present invention provides a method of treating asubject suffering from or diagnosed with a disorder mediated by PDE2activity, comprising administering to a subject in need of suchtreatment an effective amount of at least one chemical entity of thepresent invention. In a further embodiment, the subject is diagnosedwith a disorder mediated by PDE2 activity.

Chemical entities of the present invention are also useful in enhancingneuronal plasticity—an essential property of the brain that can beaugmented in healthy animals and impaired in numerous CNS disorders.Without being limited by mechanism, such chemical entities can enhancecyclic adenosine monophosphate (cAMP) response element binding protein(CREB) pathway function in cells, modulating transcription of multiplegenes involved in synaptic plasticity. See, e.g., Tully et al., Nat.Rev. Drug Discov. 2003, 2, 267-277; Alberini, Physiol. Rev. 2009, 89,121-145. Accordingly, the present invention provides a method ofenhancing neuronal plasticity, comprising administering to a subject inneed thereof an effective amount of a chemical entity of the presentinvention.

Chemical entities of the present invention are also useful as “agents”(also referred to as “augmenting agents”) to augment the efficiency oftraining protocols, which facilitate functional reorganization intargeted “domains” (or “functions”) in the brain. Training protocols canbe directed to rehabilitating or enhancing a cognitive or motorfunction. The training protocol (cognitive or motor training) inducesneuronal activity in specific brain regions and produces improvedperformance of a specific brain (cognitive or motor) function. Chemicalentities of the present invention agents act as “augmenting agents,”which shorten the time that methods of rehabilitating (or enhancing) acognitive or motor function result in improved performance or afunctional gain. Such augmented training therefore comprises a specifictraining protocol for a particular brain function, such as thatunderlying declarative memory, performance of a fine motor skill, aspecific locomotor function, language acquisition, executive function,etc., and a general administration of CREB pathway-enhancing drugs.

Neurological Disorders

Chemical entities of the present invention are useful in methods oftreating a neurological disorder, comprising administering to a subjectin need thereof an effective amount of a chemical entity of Formula (I).In a specific aspect, the methods are directed to a cognitive deficit(“cognitive impairment”) or motor deficit (“motor impairment”)associated with (or “due to”) the neurological disorder.

A neurological disorder (or condition or disease) is any disorder of thebody's nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, or the primary type of cause. The broadestdivision is between peripheral nervous system (PNS) disorders andcentral nervous system (CNS) disorders (such as mental and psychiatricdisorders). Neurological disorders are well-known in the art, and theyinclude, but are not limited to, the following mental and psychiatricdisorders:

-   -   Neurodevelopmental (or “developmental” disorders), such as        intellectual disability disorders (e.g., Rubinstein-Taybi        syndrome, Down syndrome); communication disorders;        autism-spectrum disorder; attention-deficit/hyperactivity        disorder; specific learning, language, or reading (e.g.,        dyslexia) disorders; motor disorders; fetal alcohol spectrum        disorders (FASD); and other neurodevelopmental disorders;    -   Schizophrenia spectrum and other psychotic disorders, such as        schizophrenia, schizotypal (personality) disorder, delusional        disorder, and schizophreniform disorder, and other schizophrenia        spectrum and psychotic disorders;    -   Bipolar and related disorders, such as Bipolar I and II        disorders, cyclothymic disorder, and other bipolar and related        disorders;    -   Depressive disorders, such as major depressive disorder,        persistent depressive disorder (dysthymia), and other depressive        disorders;    -   Anxiety disorders, such as specific phobias, social anxiety        disorder (social phobia), panic disorder, generalized anxiety        disorder (GAD), posttraumatic stress disorder (PTSD), and other        anxiety disorders;    -   Obsessive-compulsive and related disorders, such as        obsessive-compulsive disorder, body dysmorphic disorder, and        other obsessive-compulsive and related disorders;    -   Dissociative disorders, such as dissociative identity disorder,        dissociative amnesia, and other dissociative disorders;    -   Disruptive, impulse-control, and conduct disorders, such as        conduct disorders, antisocial personality disorder, and other        disruptive, impulse-control, and conduct disorders;    -   Trauma- and stressor-related disorders, such as posttraumatic        stress disorder, adjustment disorders, and other trauma- and        stressor-related disorders;    -   Feeding and eating disorders, such as anorexia, bulimia,        binge-eating disorder, and other feeding and eating disorders;    -   Sleep-wake disorders, such as insomnia, narcolepsy, parasomnias,        and other sleep-wake disorders;    -   Sexual disorders, such as arousal disorders, desire disorders,        substance and medication-induced dysfunctions, and other sexual        disorders;    -   Substance-related and addictive disorders, such as those        involving alcohol, drugs, stimulants, opioids, tobacco, and        non-substance-related disorders; and other substance-related and        addictive disorders; and    -   Personality disorders, such as paranoid personality disorder,        antisocial personality disorder, borderline personality        disorder, avoidance personality disorder, and other personality        disorders; and    -   In particular embodiments, the disorder is schizophrenia, an        attention deficit disorder, or an anxiety disorder.

In other embodiments, the neurological disorder is an acquired disorder,in which the primary clinical feature is impaired cognition. In otherwords, it is a disorder in which the primary cognitive deficit has notbeen present since birth or very early life and therefore represents adecline from a previously attained level of functioning. Such disorders,which may be referred to herein as “cognitive disorders” or“neurocognitive disorders” include one or more of the following:

-   -   Delirium, such as substance-intoxication (or withdrawal)        delirium, medication-induced delirium, and other forms of        delirium;    -   Dementias and other cognitive impairments due to HIV infection        or due to neurodegenerative diseases, such as Alzheimer's        disease, Parkinson's disease, Huntington's disease, Lewy body        disease, Pick's disease, a prion disease (e.g.,        Creutzfeldt-Jakob disease), Amyotrophic lateral sclerosis (ALS),        multiple sclerosis, frontotemporal lobar degeneration, and        corticobasal degeneration; dementia due to a vascular disease        (“vascular disease”); and other dementias and neurodegenerative        diseases;    -   Age-associated cognitive deficits, including age-associated        memory impairment (AAMI), also referred to as age-related memory        impairment (AMI) (See, e.g., Crook et al., Devel. Neuropsychol.        1986, 2, 261-276); and deficits affecting patients in early        stages of cognitive decline, as in Mild Cognitive        Impairment (MCI) (See, e.g., Arnáiz and Almkvist, Acta Neurol.        Scand. Suppl. 2003, 179, 34-41), and;    -   Trauma-dependent losses of cognitive function, such as vascular        diseases due to stroke (e.g., ischemic or hemorrhagic stroke) or        ischemia; microvascular disease arising from diabetes or        arthrosclerosis; traumatic brain injury (TBI), such as brain        trauma, including subdural hematoma and brain tumor; head trauma        (closed and penetrating); head injury; tumors, such as nervous        system cancers, including cerebral tumors affecting the thalamic        or temporal lobe; hypoxia; and viral infection (e.g.,        encephalitis); excitotoxicity; and seizures; and    -   Cognitive impairments due to chemotherapy, such as        post-chemotherapy cognitive impairments (PCCI);        chemotherapy-induced cognitive dysfunction or impairments; chemo        brain; or chemo fog.

Such acquired disorders are not necessarily limited to cognitiveimpairments. For example, trauma related disorders, such as stroke,traumatic brain injury, head trauma, and head injury, may also includeimpairments in other neurological functions, such as impairments inmotor functions.

As used herein, the terms “Neurodevelopment disorders,” “Schizophreniaspectrum and other psychotic disorders,” Bipolar and related disorders,”“Depressive disorders,” “Anxiety disorders,” “Obsessive-compulsive andrelated disorders,” “Dissociative disorders,” “Disruptive,impulse-control, and conduct disorders,” “Trauma- and stressor-relateddisorders,” “Feeding and eating disorders,” “Sleep-wake disorders,”“Sexual disorders,” “Substance-related and addictive disorders,”“Personality disorders,” “Delirium,” “Neurocognitive disorders,”“Delirium,” “Dementias,” and “Trauma” include treatment of those mentaldisorders as described in the Diagnostic and Statistical Manual ofMental Disorders (DSM-5; 5^(th) ed., 2013, American PsychiatricAssociation). The skilled artisan will recognize that there arealternative nomenclatures and classification systems for mentaldisorders, and that these systems evolve with medical and scientificprogress. Thus the terms described in this paragraph are intended toinclude like disorders that are described in other diagnostic sources.

In other embodiments, the neurological disorder is a movement or motordisorder, a group that includes, but is not limited to: kinesias andakinetic-rigid syndromes, such as Parkinson's disease or corticobasaldegeneration; Tourette's syndrome, epilepsy, muscular spasms, anddisorders associated with muscular spasticity or weakness; dyskinesias,including tremors, such as rest tremor, postural tremor and intentiontremor); chorea, such as that in Huntington's disease; myoclonus(including generalized myoclonus and focal myoclonus); tics (includingsimple tics, complex tics and symptomatic tics); dystonia; restless legsyndromes; Wilson's Disease; Hallerworden-Spatz disease; basal gangliadisorders; hyperkinetic, hypokinetic, and dyskinetic disorders; movementdisorders induced by drugs; and other movement and motor disorders.

Augmented Training

In certain embodiments, chemical entities of the present inventionprovide augmenting agents to enhance the efficiency of trainingprotocols, including cognitive training and motor training protocols.Such methods are known as “augmented training,” and, more particularly,“augmented cognitive training” or “augmented motor training.”

Training (or a “training protocol”) generally requires many sessions toattain the desired benefits, for example, to rehabilitate a motordeficit or language deficit following stroke. This can be costly andtime-consuming, deterring subject compliance and the realization of realworld benefits that endure over time. The efficiency of such trainingprotocols can be improved by administering certain agents (known asaugmenting agents) in conjunction with the training protocol. (See,e.g., U.S. Pat. No. 7,868,015; U.S. Pat. No. 7,947,731; US2008-0188525). When administered in combination with training protocols(or “training”), augmenting agents enhance functional reorganization intargeted domains (or “functions”) in the brain.

Cognitive domains (or functions) that can be targeted by trainingprotocols include, but are not limited to, the following: attention(e.g., sustained attention, divided attention, selective attention,processing speed); executive function (e.g., planning, decision, andworking memory); learning and memory (e.g., immediate memory; recentmemory, including free recall, cued recall, and recognition memory; andlong-term memory, which can be divided into explicit memory (declarativememory) memory, such as episodic, semantic, and autobiographical memory,and into implicit memory (procedural memory)); language (e.g.,expressive language, including naming, word recall, fluency, grammar,and syntax; and receptive language); perceptual-motor functions (e.g.,abilities encompassed under visual perception, visuo-constructional,perceptual-motor praxis, and gnosis); and social cognition (e.g.,recognition of emotions, theory of mind). In specific embodiments, thecognitive function is learning and memory, and more particularly, longterm memory.

Motor domains (or functions) that can be targeted by training protocolsinclude, but are not limited to, those involved in gross body control,coordination, posture, and balance; bilateral coordination; upper andlower limb coordination; muscle strength and agility; locomotion andmovement; motor planning and integration; manual coordination anddexterity; gross and fine motor skills; and eye-hand coordination.

Training Protocols

Training protocols (or “modules”) are well known in the art andtypically comprise a set of distinct exercises that can beprocess-specific or skill-based: See, e.g., Kim et al., J. Phys. Ther.Sci. 2014, 26, 1-6; Allen et al., Parkinsons Dis. 2012, 2012, 1-15;Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108, 10081-10086; Cheinet al., Psychon. Bull. Rev. 2010, 17, 193-199; Klingberg, Trends Cogn.Sci. 2010, 14, 317-324; Owen et al., Nature 2010, 465, 775-778; Tsao etal., J. Pain 2010, 11, 1120-1128; Lustig et al., Neuropsychol. Rev.2009, 19, 504-522; Park and Reuter-Lorenz, Ann. Rev. Psych. 2009, 60,173-196; Oujamaa et al., Ann. Phys. Rehabil. Med. 2009, 52, 269-293;Frazzitta et al., Movement Disorders 2009, 8, 1139-1143; Jaeggi et al.,Proc. Natl. Acad. Sci. USA 2008, 105, 6829-6833; Volpe et al.,Neurorehabil. Neural Repair 2008, 22, 305-310; Fischer et al., Top.Stroke Rehab. 2007, 14, 1-12; Jonsdottir et al., Neurorehabil. NeuralRepair 2007, 21, 191-194; Stewart et al., J. Neurol. Sci. 2006, 244,89-95; Krakauer, Curr. Opin. Neurol. 2006, 19, 84-90; Belleville et al.,Dement. Geriatr. Cogn. Disord. 2006, 22, 486-499; Klingberg et al., J.Am. Acad. Child. Adolesc. Psychiatry 2005, 44, 177-186; Dean et al.,Arch. Phys. Med. Rehabil. 2000, 81, 409-417; Whitall et al., Stroke2000, 31, 2390-2395; Hummelsheim and Eickhof, Scand. J. Rehabil. Med.1999, 31, 250-256; Merzenich et al., Science 1996, 271, 77-81; Merzenichet al., Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 1-8; Rider andAbdulahad, Percept. Mot. Skills 1991, 73, 219-224.

Process-specific training focuses on improving a particular domain suchas attention, memory, language, executive function, or motor function.Here the goal of training is to obtain a general improvement thattransfers from the trained activities to untrained activities based onthe same cognitive or motor function or domain.

Skill-based training is aimed at improving performance of a particularactivity or ability, such as learning a new language, performing amusical instrument, improving memory, or learning a fine motor skill.The different exercises within such a protocol will focus on corecomponents within one or more domains underlying the skill. Modules forincreasing memory, for example, may include tasks directed to specificdomains involved in memory processing, e.g., the recognition and use offact, and the acquisition and comprehension of explicit knowledge rules.

In some embodiments, the battery of exercises is administered as part ofa single training session. In one aspect, the training protocolcomprises multiple training sessions, each separated by a discreteinterval. In another aspect, the number of training sessions sufficientto improve performance is reduced compared to that produced by trainingalone.

In a further aspect, the augmenting agent is a PDE2 inhibitor, and moreparticularly, is a chemical entity of the present invention, and isadministered in conjunction with training. By “in conjunction” is meantthat the augmenting agent enhances CREB pathway function duringtraining. In some embodiments, the deficit is a motor deficit. In otherembodiments, the deficit is a cognitive deficit. In still otherembodiments, the deficit may include both a cognitive and motor deficit.In other aspects, the compound is administered before and during eachtraining session. In one aspect, the subject is a human. In someembodiments, the subject is a non-human, and more particularly, is aprimate or a canine.

In one aspect, a compound or composition of the present invention can beused as an augmenting agent in conjunction with any psychotherapeuticapproach intended to modulate cognitive function in the brain, therebyenhancing the efficacy of such therapy by reducing the number ofsessions necessary to attain benefits.

Stroke

In some embodiments, chemical entities and compositions of the presentinvention are useful in treating stroke, and in more specificembodiments, treating motor or cognitive impairments during post-strokerehabilitation. Stroke care is a temporal continuum that includesimmediate (acute) treatments and subsequent rehabilitative therapy.

Acute treatments directly target the initial damage, such as thattriggered by ischemic or hemorrhagic stroke; they usually involve usingagents to dissolve clots and restore blood flow to reduce tissue damageand stabilize the patient. The efficacy of acute treatments is typicallylimited to a short time window extending only a few hours from strokeonset.

The focus of stroke treatment shifts to rehabilitation after the patienthas been medically stabilized. Rehabilitation (also referred to as“stroke rehabilitation” or “post-stroke rehabilitation”) is directed tocognitive and motor deficits that persist after the initial strokeinjury, the goal being to restore and recover neurological function asmuch as possible to compensate for the permanent tissue loss (e.g., 1995Clinical Guideline by the Department of Health and Human Services onPost-Stroke Rehabilitation).

Stroke rehabilitation is typically a comprehensive program coordinatedby a team of medical professionals. A physical therapist on the team,for example, may focus on maintaining and restoring range of motion andstrength in affected limbs, maximizing mobility in walking, improvingmanual dexterity, and rehabilitating other motor and sensorimotorfunctions. A mental health professional may be involved in the treatmentof loss of cognitive skills. Rehabilitation services can occur inmultiple environments, such as a rehabilitation hospital, long-term carefacility, outpatient clinic, or at home.

Neurological functions impacted by stroke (and which can be targetedduring rehabilitation) include impairments in cognitive and motorfunctions. Cognitive function impairments, for example, can manifest asdeficits in understanding speech or writing (aphasia); knowing the rightwords but having trouble saying them clearly (dysarthria); as well asdeficits in other cognitive functions, such as attention, reasoning,planning, execution, and learning and memory. Motor functionimpairments, for example, can manifest as weakness (hemiparesis) orparalysis (hemiplegia) on one side of the body that may affect the wholeside or just the arm or leg; by problems with balance or coordination;deficits in gross motor skills such as gait and walking speed; deficitsin fine motor skills or manual dexterity; and deficits in upper andlower extremity function.

Accordingly, the present invention provides the use of a PDE2 inhibitorin the treatment of stroke, including post stroke rehabilitation. Incertain embodiments, chemical entities of the present invention areuseful during stroke rehabilitation to treat stroke deficits (or“post-stroke deficits”) resulting from impaired neurological functions.In some embodiments, the present invention provides methods of treatinga neurological deficit during post-stroke rehabilitation comprising: (a)administering to a subject in need thereof a PDE2 inhibitor duringrecovery of the subject from stroke; (b) providing training to thesubject under conditions sufficient to improve performance of aneurological function whose impairment is due to the deficit; and (c)repeating steps (a) and (b) one or more times, whereby the amount oftraining sufficient to improve the performance is reduced compared tothat produced by training alone.

In one aspect, the PDE2 inhibitor is a chemical entity of the presentinvention. In some embodiments, the deficit is a motor deficit. In otherembodiments, the deficit is a cognitive deficit, particularly, a deficitin memory formation, and more specifically, a deficit in long-termmemory formation. In still other embodiments, the deficit may include acognitive and motor deficit. In another aspect, training comprises abattery of tasks directed to the neurological function. In a specificaspect, the reduction in the amount of training is a reduction in thenumber of training sessions.

In a further embodiment, said administering step (a) is in conjunctionwith said training step (b). In one aspect, the subject is a human. Inanother aspect, the subject has undergone neuronal stem cellmanipulation. In other aspects, the compound is administered before andduring each training session.

Traumatic Brain Injury

In some embodiments, chemical entities and compositions of the presentinvention are useful in treating traumatic brain injury, and in morespecific embodiments, treating motor or cognitive impairments duringrehabilitation after the initial trauma. Like stroke care, TBI case is atemporal continuum that includes immediate (acute) treatments andsubsequent rehabilitative therapy.

Accordingly, the present invention provides the use of a PDE2 inhibitorin the treatment of TBI, including during TBI rehabilitation to treatTBI deficits (or “post-TBI deficits”) resulting from impairedneurological functions. In some embodiments, the present inventionprovides methods of treating a neurological deficit during post-TBIrehabilitation comprising: (a) administering to a subject in needthereof a PDE2 inhibitor during recovery of the subject from TBI; (b)providing training to the subject under conditions sufficient to improveperformance of a neurological function whose impairment is due to thedeficit; and (c) repeating steps (a) and (b) one or more times, wherebythe amount of training sufficient to improve the performance is reducedcompared to that produced by training alone.

In one aspect, the PDE2 inhibitor is a chemical entity of the presentinvention. In some embodiments, the deficit is a motor deficit. In otherembodiments, the deficit is a cognitive deficit, particularly, a deficitin memory formation, and more specifically, a deficit in long-termmemory formation. In still other embodiments, the deficit may include acognitive and motor deficit. In another aspect, training comprises abattery of tasks directed to the neurological function. In a specificaspect, the reduction in the amount of training is a reduction in thenumber of training sessions.

In a further embodiment, said administering step (a) is in conjunctionwith said training step (b). In one aspect, the subject is a human. Inanother aspect, the subject has undergone neuronal stem cellmanipulation. In other aspects, the compound is administered before andduring each training session.

Peripheral Disorders

Chemical entities of the present invention are useful in methods oftreating peripheral disorders, that is, disorders other than a primaryneurological disorder. These uses are supported by PDE2A expressionstudies and other observations. See, e.g., Bayer Healthcare AG, Intl.Pat. Appl. Publ. WO/2004/044234, May 27, 2004; Donzeau-Gouge et al.,2001, J. Physiol. 533, 329-340; Herring et al., 2001, Card. Res. 52:446-453; Keravis et al., 2000, J Vasc. Res. 37, 235-249; Wolda et al.,1999, J. Histochem. Cytochem. 47, 895-906; Dickinson et al., 1997,Biochem. J. 323: 371-377; Fischmeister et al., 1997, J Clin. Invest. 99,2710-2718; Houslay et al., 1996, Cell. Signal. 8, 97-110; and Haynes etal., 1996, J. Pharm. Exp. Ther., 276, 752-757.

Accordingly, the present invention provides methods of treating aperipheral disorder, comprising administering to a subject in needthereof an effective amount of a chemical entity of Formula (I).Peripheral disorders include, but are not limited to, infectiousdiseases, such as bacterial, fungal, protozoan, and viral infections;hematological diseases, such as anemias, myeloproliferative disorders,hemorrhagic disorders, leukopenias, eosinophilic disorders, leukemias,lymphomas, and plasma cell dyscrasias; cardiovascular diseases such ascongestive heart failure, myocardial infarction, ischemic diseases,atrial and ventricular anhythmias, hypertensive vascular diseases, andatherosclerosis; gastroenterological disorders, such as diseases of theesophagus, stomach, duodenum, pancreas, bowel, and liver; dermatologicaldisorders, such as psoriasis, dermatitis, impetigo, folliculitis,melanoma; and other peripheral disorders, including renal diseases, inparticular kidney failure, and inflammatory diseases.

Animal Skill Training Protocols

In some embodiments, chemical entities of the present invention are usedto enhance the efficiency of training protocols directed to cognitiveand motor skills in an animal. Such augmented training reduces the timenecessary to acquire or enhance a cognitive or motor skill in thenon-human animal.

In particular embodiments, the animal is a non-human animal, and moreparticularly, is a service animal, a category that includes, but is notlimited to, dogs, miniature horses, and capuchin monkeys. Serviceanimals may be involved in public service or private service, and thetraining protocols will be appropriately matched to these objections.For example, training protocols directed to public service includepublic order maintenance, search and rescue, and contraband detection,and training protocols directed to private service include privatesecurity, handicap assistance, health care, psychiatric assistance, andpest control.

The training protocol may be directed to a single skill, such as thedetection of a single drug in a service animal. In other embodiments,the training protocol may be directed to a complex set of skills, suchas those underlying search and rescue training of a service animal; fora complex set of skills, training will therefore comprise more than onetask.

Accordingly, in some embodiments, the present invention provides amethod of teaching a non-human animal one or more skills, comprising (a)administering to a non-human animal in need thereof a PDE2 inhibitor;(b) providing training to the animal under conditions sufficient toimprove performance of said one or more skills; and (c) repeating steps(a) and (b) one or more times, whereby the amount of training sufficientto improve the performance is reduced compared to that produced bytraining alone.

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

Synthetic Schemes

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −78° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

According to Scheme A, commercially available or syntheticallyaccessible 5-hydroxynicotinic acid is reacted under esterificationconditions, for example by treating an alcohol solution of5-hydroxynicotinic acid with an acid, at elevated temperatures, for aperiod of 24 h to 7 days. In a preferred method 5-hydroxynicotinic acidis dissolved in MeOH, treated with H₂SO₄, and heated at reflux for aperiod of 7 days, to afford methyl 5-hydroxynicotinate. Hydrogenation ofmethyl 5-hydroxynicotinate, in the presence of a palladium catalyst suchas Pd/C, H₂ under pressure, in a solvent such as AcOH, at temperaturesranging from rt to 60° C., affords methyl5-hydroxypiperidine-3-carboxylate. Methyl5-hydroxypiperidine-3-carboxylate is protected with a suitableprotecting group such as BOC. In a preferred method, treating an alcoholsolution of methyl 5-hydroxypiperidine-3-carboxylate with a base such asTEA, and the like, di-tert-butyl dicarbonate (BOC₂O), a roomtemperature, for a period of 8 to 24 h, provides a compound of formula(II). Oxidation of a compound of formula (II), under conditions known toone skilled in the art, such as Swern oxidation conditions, provides acompound of formula (III). A compound of formula (III) is treated underfluorination conditions known to one skilled in the art, for example,reaction with a fluorinating agent such as DAST®, Deoxo-Fluor®, and thelike, in a solvent such as DCM. Subsequent saponification offluoropiperidines under conditions known to one skilled in the art,provides a piperidine acid compound of formula (IV).

According to Scheme B, a cyanomorpholine compound of formula (VI) iscommercially available or are prepared in two steps, using conventionalsynthetic methods as previously described in OPRD, 2004, 13(2), 209-224.For example, commercially available or synthetically accessible2-aminoethanol compounds of formula (V), where PG is benzyl, is reactedin a Michael addition with 2-chloroacrylonitrile, in a solvent such astoluene, Et₂O, and the like, at temperatures ranging from −5° C. to 40°C., for a period of 1 to 24 h. Subsequent cyclization is achieved byreaction with a base such as t-BuOK, and the like, in a solvent such asTHF, toluene, or a mixture thereof, at temperatures ranging from −5° C.to 15° C., for a period of 1 to 3 h. A cyanomorpholine compound offormula (VI) is hydrolyzed to a morpholine carboxylic acid compound offormula (VII), under acidic conditions, for example, in the presence ofan acid such as HCl, H₂SO₄, and the like, in a solvent such as toluene,H₂O, or a mixture thereof, at temperatures ranging from rt to 95° C.,for a period of 1 to 5 h, to provide a compound a formula (VII).

According to Scheme C, a compound of formula (XI), where PG is Cbz, BOC,and the like, is prepared from an enolate compound of formula (VIII) andan acid chloride compound of formula (X). Reaction of commerciallyavailable or synthetically accessible tert-butyl 3-oxobutanoate withmethylmagnesium chloride, and the like, in a solvent such as THF, at atemperature of 0° C., followed by addition of an acid chloride compoundof formula (X), which is prepared using methods known to one skilled inthe art, at temperatures ranging from 0° C. to room temperature, for aperiod of 1 to 24 h provides a compound of formula (XI). Acid catalyzedester hydrolysis/decarboxylation of a compound of formula (XI) with anacid such as p-toluenesulfonic acid, and the like, in a solvent such astoluene, at temperatures ranging from 70° C. to 100° C., for a period of6 to 16 h, provides a compound of formula (XII).

According to Scheme D, a compound of formula (XV), where PG is BOC, isobtained in two steps by first reaction of fluoropiperidines of formula(XIII) with a suitable heteroaryl of formula (XIV), where R² isC₁₋₆alkyl, a base such as LiHMDS, NaHMDS, LDA, NaH, and the like, in asolvent such as THF, DCM, DME and the like, at temperatures of about −78to 0° C., for a period of about 30 min to 2 h. In a preferred method, acompound of formula (XIII) is reacted with a compound of formula (XIV),LiHMDS, in THF, at −78° C., for a period of 45 minutes. Subsequentdecarboxylation, under conditions known to one skilled in the art, forexample, employing a base such as LiOH, in a solvent such as MeOH, H₂Oor a mixture thereof, at temperatures ranging from 0-25° C., for aperiod of 16 to 24 h, provides a compound of formula (XV).

According to Scheme E, activation of a commercially available orsynthetically accessible compound of formula (XVI), where Y is —CH₂— or—CF₂—; X is —CH₂— or —O—; and PG is a suitable protecting group such asBn, CBz or BOC, with a reagent such as CDI, followed by reaction withthe enolate of a compound of formula R²—C(═O)CH₃, where R² is—C₁₋₆alkyl, and the like, (prepared by the reaction of LDA which isprepared insitu by reaction of diisopropylamine with n-BuLi, in asolvent such as THF, at temperatures of about −70° C., for a period of 1hr), at temperatures of about −60° C., for a period of 1 h, provides adiketo compound of formula (XVII). In a similar fashion, a compound offormula R²—C(═O)CH₃, where R² is —C₁₋₆alkyl substituted with on or more—F members may be employed. Condensation of 1H-1,2,4-triazol-5-aminewith a diketo compound of formula (XVII) in a solvent such as AcOH, attemperatures ranging from 80° C. to 100° C., for a period of 8 to 24 h,provides a compound of formula (XVIII). Removal of the protecting group(PG), is accomplished by using methods known to one skilled in the art.For example, removal of the tert-butylcarbamate (BOC) protecting group(PG) in a compound of formula (XVIII) is accomplished by using HCl, TFA,or p-toluenesulfonic acid, in a solvent such as MeOH, dioxane, orCH₂Cl₂. In a preferred embodiment, a compound of formula (XVIII) istreated with TFA or HCl in DCM, to provide a compound of formula (XIX).

A compound of Formula (I), where Z is —C(═O)—, is obtained by subsequentreaction of an amine of formula (XIX) with a suitable acid of formulaR¹—CO₂H under amide forming conditions. A compound of formula R¹—CO₂H,where R¹ is as defined in Formula (I), is commercially available, asdescribed, or a synthetically accessible appropriately substituted aryl,cycloalkyl or heteroaryl carboxylic acid. In a preferred embodiment acompound of formula (XIX), where R² is —CH₃, either as a free base or asan acid salt, is reacted with a compound of formula R¹—CO₂H, in thepresence of a dehydrating agent such as HOBt/EDAC, HATU, HOAT; asuitably selected base such as DIPEA, TEA, and the like; in an organicsolvent or mixture thereof, such as toluene, acetonitrile, ethylacetate, DMF, THF, methylene chloride, and the like; to afford acompound of Formula (I). In a particularly preferred embodiment thedehydrating agent is HATU, and the base is DIPEA.

In an alternative embodiment, a compound of formula R¹—CO₂H (asdescribed above) may be first converted to a compound of formulaR¹—COCl, or compound of formula R¹—COCl is a commercially availablesubstituted aryl chloride. A compound of formula R¹—CO₂H may be treatedwith thionyl chloride in a solvent such as toluene to afford a compoundof formula R¹—COCl. A compound of Formula (I) is obtained by treating acompound of formula R¹—COCl with a compound of formula (XIX), a suitablyselected tertiary organic base such as TEA, and the like, in a solventsuch as DCM, THF, and the like, at a temperature between roomtemperature and the reflux temperature of the solvent, to afford acompound of Formula (I)

A compound of Formula (I), where Z is —CH₂—, is obtained by subsequentreaction of the amines of formula (XIX) with a suitable aldehyde offormula R¹—CHO under reductive amination conditions. Compounds offormula R¹—CHO, where R¹ is as defined in Formula (I), are commerciallyavailable, as described, or synthetically accessible appropriatelysubstituted aryl, cycloalkyl or heteroaryl aldehydes. In a preferredembodiment a compound of formula (XIX), either as a free base or as anacid salt, is reacted with a compound of formula R¹—CHO, in the presenceof a reducing agent, such as sodium triacetoxyborohydride, sodiumcyanoborohydride and the like, in a solvent such as THF, DCM, MeOH andthe like, at temperatures ranging from 0 to 50° C., for a period of 1 to4 h, to provide a compound of Formula (I).

A compound of Formula (I), is deuterated by treating a non-deuteratedcompound of Formula (I), with deuterated solvent, such as CD₃OD, in thepresence of a base, such as DIEA, at temperatures ranging from roomtemperature to 50° C., for a period of 18 to 100 h. Exemplarypreparations are given in the Examples. The level of deuteration can bedetermined by NMR analysis and by mass spectrometry.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution. Wherethe compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

Examples

Chemistry:

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated,” theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on Silica(SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

LC/MS were obtained on a Waters 2695 Separations Unit, 2487 DualAbsorbance Detector, Micromass ZQ fitted with ESI Probe, or a WatersAcquity™ Ultra performance LC (UPLC) with PDA eλ and SQ detectors.

Preparative HPLC was performed on a Shimadzu SIL-10AP system using aWaters SunFire™ OBD 30 mm×100 mm×2.5 μm (particle size) C¹⁸ column witha 15 minute gradient of 10-100% acetonitrile in water and 0.05%trifluoroacetic acid added as a modifier to both phases. Elutionprofiles were monitored by UV at 254 and 220 nm.

Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuteratedacetone ((CD₃)₂CO)), chloroform (CDCl₃), methanol-d₄ (CD₃OD), ordimethyl sulfoxide-d₆ (DMSO-d₆). For CDCl₃ samples, the residual centralresonance peak at 7.26 for ¹H was used for chemical shift assignment for¹H NMR spectra. For CD₃OD the residual central resonance peak at 3.31for ¹H was used for chemical shift assignment and for DMSO-d₆ theresidual central resonance peak at 2.50 ppm for ¹H was used for chemicalshift assignment. The format of the ¹H NMR data below is: chemical shiftin ppm downfield the tetramethylsilane reference (multiplicity, couplingconstant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ChemAxon.

Intermediate 1.2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholine

Step A. 4-Benzylmorpholine-2-carbonitrile. 2-(Benzylamino)ethanol (46 g,304 mmol) and 2-chloroacrylonitrile (26.5 g, 304 mmol) were stirred atrt for 18 h. THF (300 mL) was added followed by t-BuOK (38.9 g, 330mmol) portionwise over 1 h, keeping the reaction temperature at <2° C.After 1 h post-stirring at 0° C., the mixture was quenched with sat. aq.NaHCO₃. The aqueous layer was extracted with EtOAc. The organic layerwas dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification (FCC, SiO₂, (PE/EtOAc=5/1) provided the title compound (45g, 73%) as an oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.36-7.27 (m, 5H),4.63-4.60 (m, 1H), 4.15-4.00 (m, 1H), 3.82-3.75 (m, 1H), 3.64-3.53 (m,2H), 2.80-2.75 (m, 1H), 2.67-2.54 (m, 2H), 2.46-2.39 (m, 1H).

Step B. 4-Benzylmorpholine-2-carboxylic acid. To a solution of4-benzylmorpholine-2-carbonitrile (20.2 g, 100 mmol) in toluene (60 mL)was added 6M HCl (100 mL, 600 mmol). The reaction mixture was refluxedat 110° C. for 1.5 h and then cooled to rt and stirred for 18 h. Thesolid was filtered to give the title compound (22 g, 99%) as a whitesolid.

Step C. 1-(4-Benzylmorpholin-2-yl)butane-1,3-dione. To a solution ofi-Pr2NH (7 mL, 50 mmol) in THF (40 mL) was added n-BuLi (20 mL, 50 mmol)at 0° C. and stirred for 0.5 h. The solution was cooled to −78° C.,acetone (2.9 g, 50 mmol) was added drop wise mixture was allowed to stirat −78° C. for 1 h. A solution of 4-benzylmorpholine-2-carboxylic acid(5.52 g, 25 mmol) in THF (40 mL) with CDI (4.48 g, 27.5 mmol) stirredfor 3 h, was added drop wise at −78° C. The mixture was stirred for 1 h,and allowed to warm to rt, then neutralized with 10% critic acid. Theorganic mixture was extracted with EtOAc and the organic phase waswashed with and aq. NaHCO₃, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. Purification (FCC, SiO₂, PE/EtOAc, 5/1) affordedthe title compound (3.5 g, 53%) as a colorless oil. ¹H NMR (CDCl₃, 400MHz) δ 7.25-7.19 (m, 5H), 5.77 (s, 1H), 4.06-4.03 (d, 1H), 3.88-3.84 (d,1H), 3.66-3.60 (m, 1H), 3.50-3.41 (m, 2H), 3.01-2.97 (d, 1H), 2.61-2.58(d, 1H), 2.16-2.10 (m, 2H), 2.02-1.97 (m, 4H).

Step D.4-Benzyl-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholine. Toa solution of 1-(4-benzylmorpholin-2-yl)butane-1,3-dione (3.4 g, 13mmol) in HOAc (10 mL) was added 4H-1,2,4-triazol-3-amine (1.1 g, 13mmol). The reaction mixture was refluxed at 125° C. for 1 h and thencooled to rt. Water was added and the mixture was extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure. Purification (FCC, SiO₂, PE/EtOAc, 2/1) provided thetitle compound (3.5 g, 87%) as a white solid upon concentrating to asmall volume. ¹H NMR (CDCl₃, 400 MHz): δ 8.33 (s, 1H), 7.29-7.18 (m,5H), 7.07 (s, 1H), 5.29-5.26 (d, 1H), 4.00-3.96 (m, 1H), 3.87-3.81 (m,1H), 3.65-3.62 (d, 1H), 3.52-3.48 (d, 1H), 3.42-3.38 (d, 1H), 2.72-2.68(d, 1H), 2.64 (s, 3H), 2.25-2.19 (m, 1H), 2.04-1.98 (m, 1H).

Step E. 2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholine. Toa solution of4-benzyl-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholine(309 mg, 1.0 mmol) in CH₂ClCH₂Cl (3.5 mL) was added 1-chloroethylcarbonochloridate (286 mg, 2 mmol). After refluxing the mixture for 2 h,the solvent was evaporated under reduced pressure and the residue wasdissolved in MeOH. The mixture was stirred at rt for 2 h. The thesolvent was evaporated, the residue was dissolved in MeOH, and themixture was treated with Amberlyst-26® (hydroxide) and stirred for 18 h.The reaction mixture was filtered and the filtrate was evaporated underreduced pressure to give the title compound (170 mg, 77%). ¹H NMR(DMSO-d₆, 400 MHz) δ 8.60 (s, 1H), 7.20 (s, 1H), 5.11-5.08 (d, 1H),4.00-3.97 (d, 1H), 3.76-3.70 (m, 1H), 3.47-3.44 (m, 1H), 2.83-2.75 (m,3H), 2.64 (s, 3H), 2.51-2.49 (m, 1H); [M+H]=220.

Chiral Separation:

The racemic Intermediate 1, (5 g, 22.8 mmol) was resolved to give thepure enantiomers using a preparative SFC instrument with a Chiralpak®OZ-H (2×25 cm) column and eluting with 30% 1:1 methanol:ACN (0.1%NH₄OH)/CO₂, 100 bar. Obtained were the two pure enantiomers: The firsteluted compound (0.87 mg, >99% purity, 97% ee) was determined to be the(R)-stereoconfiguration. The second eluted compound (1.1 g, >99%purity, >99% ee) was determined to be the (S)-stereoconfiguration. Thepurified enantiomers were analyzed using a Chiralpak® OZ-H (25×0.46 cm)column and eluting with 20% methanol (DEA)/CO₂, 100 bar.

Intermediate 2.5-Methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

Step A. tert-Butyl 3-(3-oxobutanoyl)piperidine-1-carboxylate. To asolution of i-Pr₂NH (372 mL, 2.6 mol) in THF (850 mL) at −78° C. wasadded n-Buli (1040 mL, 2.6 mol). After stirring the reaction mixture for1.5 h, acetone (209 mL, 2.6 mol) was added dropwise at −78° C. and themixture was stirred for an additional 1 h. At the same time, a solutionof 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (300 g, 1.3 mol)in THF (1 L) was added CDI (233.4 g, 1.44 mol) at 0° C. and stirred atroom temperature for 2 h. This solution was added drop wise at −78° C.and the resultant mixture stirred at −78° C. for 1 h and then allowed towarm to rt. The mixture was poured onto ice/water and extracted withEtOAc (2×2 L), the EtOAc layer was washed with 10% critic acid, aqueousNaHCO₃ and brine. The organic layer was dried (Na₂SO₄), concentratedunder reduced pressure and purified (FCC, SiO₂, PE) to afford the titlecompound (300 g, 43%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 5.48(s, 1H), 3.85-4.00 (m, 2H), 2.65-2.81 (m, 2H), 2.20-2.30 (m, 1H), 1.96(s, 3H), 1.82-1.87 (m, 1H), 1.49-1.62 (m, 3H), 1.36 (s, 9H).

Step B. tert-Butyl3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate.To a solution of tert-butyl 3-(3-oxobutanoyl)piperidine-1-carboxylate(150 g, 0.56 mol) in HOAc (300 mL) was added 4H-1,2,4-triazol-3-amine(47 g, 0.56 mol). The reaction mixture was refluxed at 125° C. for 2 hand then cooled to rt. Water was added and the mixture was extractedwith EtOAc (3×1 L). The organic layer was dried (Na₂SO₄), filtered andevaporated under reduced pressure. The residue was purified bycrystallization (PE/EtOAc; 50/1 to 15/1) to afford the title compound(160 g, 90%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.42 (s, 1H),6.81 (s, 1H), 4.27-4.30 (m, 1H), 3.94-3.96 (m, 1H), 3.56-3.61 (m, 1H),3.28-3.31 (m, 1H), 3.04-3.09 (m, 1H), 2.68 (s, 3H), 2.24-2.26 (m, 1H),1.70-1.89 (m, 3H), 1.45 (s, 9H).

Step C. 5-Methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine. Toa solution of tert-butyl3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate(160 g, 0.504 mol) in DCM (800 mL) was added HCl/MeOH (800 mL) Afterstirring at 30° C. for 3 h, the reaction mixture was filtered and thesolid collected and dried. The collected solid was dissolved in MeOH (1L), treated with Amberlyst-26® (hydroxide), then filtered andconcentrated. The residue was dissolved in MeOH (1 L), basified withexcessive solid Na₂CO₃, then filtered and concentrated under reducedpressure. The residue was dissolved in DCM (600 mL) and filtered toafford the title compound (50.52 g, 46.2%) as a yellow solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.53 (s, 1H), 7.16 (s, 1H), 3.48-3.54 (m, 1H),3.27-3.29 (m, 1H), 2.96-2.99 (m, 1H), 2.69-2.75 (m, 1H), 2.58 (s, 3H),2.48-2.53 (m, 1H), 2.06-2.09 (m, 1H). 1.53-1.74 (m, 3H).

Chiral Separation:

The racemic Intermediate 2, (8 g, 36.8 mmol) was resolved to give thepure enantiomers using a Shimadzu LC-20AP preparative HPLC with aChiralcel® OD 250×50 mm I.D. column and eluting with 80/20 mixture ofn-hexane and ethanol (0.05% IPAm). Obtained were the two pureenantiomers: The first eluted compound (3.2 g, 97.3% purity, 97.6% ee)was determined to be the (R)-stereoconfiguration. The second elutedcompound (3.1 g, 97.7% purity, 96.5% ee) was determined to be the(S)-stereoconfiguration. The purified enantiomers were analyzed using aShimadzu LC-20AB analytical HPLC instrument with a Chiralcel® OD-H,250×4.6 mm I.D. column and eluting with 80/20 mixture of n-hexane andethanol (0.05% IPAm).

Intermediate 3.7-(5,5-Difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

Step A. Methyl 5-hydroxynicotinate. To a solution of 5-hydroxynicotinicacid (833 g, 5.99 mol) in methanol (6.7 L) was added H₂SO₄ (292 mL)dropwise at a rate to keep the temperature of the mixture under 30° C.After addition, the reaction mixture was stirred at reflux for 7 days.The reaction mixture was cooled to rt and concentrated under reducepressure. Water (4 L) was added and the mixture adjusted to pH 8 withNaHCO₃ which induced precipitation of a white solid. After stirring thereaction mixture for 1 h at rt, the solid was filtered and dried undervacuum at 60° C. for 3 days to afford the title compound (783 g, 85%) asa white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.46 (s, 1H), 8.54 (s, 1H),8.34-8.35 (d, J=2.8 Hz, 1H), 7.59 (s, 1H), 3.85 (s, 3H).

Step B. Methyl 5-hydroxypiperidine-3-carboxylate. To a solution ofmethyl 5-hydroxynicotinate (100 g, 0.65 mol) in AcOH (1000 mL) was addedPd/C (20 g) at rt. The mixture was stirred under a hydrogen atmosphere(50 psi) at 60° C. overnight. The reaction mixture was cooled to rt andfiltered. The filtrate was concentrated under reduce pressure to affordthe title compound as a brown oil, which was used in the next stepwithout further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ 3.62 (s, 3H),2.68-2.99 (m, 4H), 2.33-2.45 (m, 1H), 2.03-2.14 (m, 2H), 1.37-1.82 (m,3H).

Step C. 1-tert-Butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate. Toa stirred solution of methyl 5-hydroxypiperidine-3-carboxylate (300 g,1.89 mol) in MeOH (3 L) was added TEA (382.5 g, 3.78 mol) and Boc₂O (412g, 1.89 mol) at 0° C. The reaction mixture was stirred overnight at rt.The reaction mixture was concentrated under reduce pressure, and dilutedwith DCM (3 L). The mixture was washed with aq. sat. critic acid (2 L).The organic layer was separated, and the aqueous layer was extractedwith DCM (3×500 mL) The combined organic layers were washed with water(1 L) and brine (500 mL), dried (Na₂SO₄), filtered, and concentratedunder reduce pressure. Purification (FCC, SiO₂, PE/EtOAc, 30:1 to 5:1)afforded the title compound (170 g, 35%) as a brown solid. ¹H NMR(CDCl₃, 400 MHz) δ 3.95-4.04 (m, 1H), 3.71 (s, 3H), 2.93-3.11 (m 2H),2.89-2.92 (m, 1H), 2.57 (bs, 1H), 2.21-2.34 (m, 1H), 2.00-2.12 (m, 1H),1.75-1.87 (m, 1H), 1.58-1.71 (m, 1H), 1.46 (s, 9H).

Step D. 1-tert-Butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate. To asolution of oxalyl chloride (98 g, 772 mmol) in anhydrous DCM (400 mL)was added a solution of DMSO (60.2 g, 772 mmol) in DCM (400 mL) dropwiseat a rate so as to keep the temperature of the mixture below −60° C.under nitrogen. After stirring for 30 min, 1-tert-butyl 3-methyl5-hydroxypiperidine-1,3-dicarboxylate (100 g, 386 mmol) was added. Themixture was stirred for 1 h at −60° C. before TEA (195.3 g, 1.93 mol)was added. The solution was further stirred for 1 h then allowed to warmto rt prior to adding ice-water (1 L). The pH of the mixture wasadjusted to 6 by adding aqueous critic acid. The organic layer wasseparated and the aqueous layer extracted with DCM (3×300 mL) Thecombined organic layer was washed with water (1 L), brine (1 L), dried(Na₂SO₄), filtered and concentrated under reduce pressure to give thecrude product as a brown oil, which was used in the next step withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz) δ 4.03 (s, 2H), 3.79-3.91(m, 2H), 3.75 (s, 3H), 3.05-3.13 (m, 1H), 2.72-2.80 (m, 1H), 2.60-2.67(m, 1H), 1.47 (s, 9H).

Step E. 1-tert-Butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate.To a solution of 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate(102 g, 396.8 mmol) in anhydrous DCM (600 mL) was added a solution ofDAST (95.8 g, 595.2 mmol) in DCM (200 mL) dropwise at −20° C. TLC(PE/EtOAc, 2:1) showed the starting material was consumed completely.The mixture was quenched with a sat. aq. NH₄Cl (1 L). The organic layerwas separated and the aqueous layer was extracted with DCM (2×300 mL)The combined organic layers were washed with water (500 mL), brine (500mL), dried (Na₂SO₄), filtered, and concentrated under reduce pressure.Purification (FCC, SiO₂, PE/EtOAc, 30:1 to 5:1) afforded the titlecompound (87 g, 78%) as a brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 4.22-4.38(m, 2H), 3.66 (s, 3H), 2.76-2.96 (m, 3H), 2.41 (bs, 1H), 1.85-2.00 (m,1H), 1.40 (s, 9H).

Step F. 1-(tert-Butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylicacid. To a solution of 1-tert-butyl 3-methyl5,5-difluoropiperidine-1,3-dicarboxylate (220 g, 0.79 mmol) in MeOH(1425 mL) and water (75 mL) was added NaOH (48 g, 1.2 mol) in portionsat 0° C. Then the reaction mixture was stirred at rt overnight. Themixture was concentrated under reduce pressure and water (1 L) wasadded. The pH value of the mixture was adjusted to 6 by critic acid. Theresulting white solid was filtered. The filter cake was collected anddried in a vacuum drying oven to afford the title compound (173 g, 83%)as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 4.17-4.32 (m, 2H), 2.76-2.92(m, 3H), 2.40-2.42 (m, 1H), 1.89-2.03 (m, 1H), 1.40 (s, 9H).

Step G. tert-Butyl3,3-difluoro-5-(3-oxobutanoyl)piperidine-1-carboxylate. To a solution ofdiisopropylamine (76 g, 754 mmol) in THF (400 mL) was addedn-butyllithium (301.6 mL, 754 mmol) dropwise at −70° C. The mixture wasstirred for 1 h at −70° C. Acetone (43.7 g, 754 mmol) was added dropwiseat −70° C. and the mixture was stirred for 1 h at −70° C. In a separateflask, to a solution of1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (100 g,377 mmol) in THF (800 mL) was added CDI (61.13 g, 377 mmol) in portionsat 0° C. The mixture was stirred for 5 h at rt and then added dropwiseto the enolate solution at −60° C. under a nitrogen atmosphere. Thereaction mixture was stirred for 1 h at −60° C., and TLC (PE/EtOAc, 3:1)showed the starting material was consumed completely. The mixture waswarmed to room temperature and EtOAc (1 L) was added. The pH value ofthe mixture was adjusted to 6 by with sat. aq. critic acid. The organiclayer was separated, and the aqueous layer was extracted with EtOAc(2×500 mL) The combined organic layer was washed with water (500 mL) andbrine (500 mL), dried (Na₂SO₄), filtered, and concentrated under reducepressure. Purification (FCC, SiO₂, PE/EtOAc, 50:1 to 3:1) afforded thetitle compound (60 g, 52%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ15.22 (br s, 1H), 5.52 (s, 1H), 4.17-4.32 (m, 2H), 2.76-2.92 (m, 3H),2.40-2.42 (m, 1H), 1.97 (s, 3H), 1.40 (s, 9H).

Step H. tert-Butyl3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate.To a solution of tert-butyl3,3-difluoro-5-(3-oxobutanoyl)piperidine-1-carboxylate (80 g, 262 mmol)in AcOH (400 mL) was added 4H-1,2,4-triazol-3-amine (22 g, 262 mmol) atrt. Then the reaction mixture was heated to 125° C. for 2 h. The mixturewas cooled to room temperature and poured into water (1 L), and wasextracted with EtOAc (3×500 mL) The combined organic layer was washedwith sat. aq. NaHCO₃ (1 L) and brine (500 mL), dried (Na₂SO₄), filtered,and concentrated under reduce pressure to give the crude product (80 g)as brown oil, which was used in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 8.44 (s, 1H), 6.85 (s, 1H),4.26-4.44 (m, 3H), 3.81 (bs, 1H), 3.32-3.39 (m, 2H), 2.70 (s, 3H), 1.49(s, 9H).

Step I.7-(5,5-Difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidineHCl salt. To a solution of tert-butyl3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate(115 g, 325.8 mmol) in EtOAc (200 mL) was added a solution of 4Nhydrochloric acid in EtOAc (600 mL) at 0° C. Then the reaction mixturewas stirred for 3 h at rt. The resulting white precipitate was filtered,and the filter cake was collected, and used crude in the next step.

Step J.7-(5,5-Difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine.7-(5,5-Difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidineHCl salt was mixed with DCM (500 mL) and TEA (200 mL) at 0° C. Afterstirring for 3 h the reaction mixture became homogeneous. Water (300 mL)was added and the organic layer separated. The aqueous layer wasextracted with DCM (3×100 mL) The combined organic layer was washed withbrine (300 mL), dried (Na₂SO₄), filtered, and concentrated under reducepressure to afford the title compound (92 g) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.58 (s, 1H), 7.25 (s, 1H), 3.77 (t, J=11.2 Hz,1H), 3.15-3.23 (m, 1H), 3.09-3.15 (m, 1H), 2.84-2.92 (m, 2H), 2.66-2.72(m, 1H), 2.59 (s, 3H), 2.32-2.36 (m, 2H); [M+H]=254.1.

Method B.

Step A. tert-Butyl3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate.To a solution of 1-tert-butyl 3-methyl5,5-difluoropiperidine-1,3-dicarboxylate (58.0 g, 207.6 mmol) in THF(1038 mL, 0.2M) cooled to −78° C. was added LiHMDS (207.6 mL, 207.6mmol, 1M in THF) dropwise over 16 min. The reaction mixture was stirredat −78° C. for 45 min. before7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine (35.0 g, 207.61 mmol)was added. The reaction mixture temperature was raised to 0° C. andstirred for 25 min. Water (32 mL), MeOH (67 mL) and LiOH (4260 mg,1245.7 mmol) were added and the reaction mixture was stirred at 0-25° C.for 18 h. The reaction mixture was diluted with DCM (500 mL) andquenched with H₂O (500 mL) The aqueous layer was extracted withdichloromethane (2×500 mL) and the combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure.Purification (LC, EtOAc/MeOH/Hexane 45:5:50) afforded the title compound(62.8 g, 86%) as a yellow foam. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s,1H), 7.27 (s, 1H), 4.37 (d, J=13.3 Hz, 1H), 4.18 (br s, 1H), 3.69-3.80(m, 1H), 3.37 (d, J=19.6 Hz, 1H), 3.20 (br s, 1H), 2.50-2.66 (m, 5H);[M+H]=354.4.

Step B.7-(5,5-Difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine.To a solution of tert-butyl3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate(62.8 g, 177.7 mmol) in MeOH (444 mL, 0.4 M) cooled to 0° C. was slowlyadded 4N HCl in dioxane (600 mL) The mixture was stirred at 0-25° C. for4 h and concentrated under reduced pressure to afford the title compound(58.1 g, 100%) as a beige solid (bis HCl salt). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.12 (br s, 1H), 9.87 (br s, 1H), 8.65 (s, 1H), 7.31 (s,1H), 4.08 (tt, J=12.4, 3.6 Hz, 1H), 3.76-3.87 (m, 1H), 3.46-3.66 (m,2H), 3.31-3.42 (m, 1H), 2.54-2.76 (m, 5H); [M+H]=254.4.

Chiral Separation:

The racemic Intermediate 3, (3.97 g, 15.3 mmol) was resolved to give thepure enantiomers using a preparative SFC instrument with a Chiralpak®OZ-H (2×25 cm) column and eluting with 25% 1:1 MeOH:ACN (0.1%NH₄OH)/CO₂, 100 bar. Obtained were the two pure enantiomers: The firsteluted compound (0.51 mg, >99% purity, >99% ee) was determined to be the(R)-stereoconfiguration. The second eluted compound (0.5 g, >99%purity, >99% ee) was determined to be the (S)-stereoconfiguration. Thepurified enantiomers were analyzed using a Chiralpak® OZ-H (25×0.46 cm)column and eluting with 30% methanol/CO₂, 100 bar.

Example 1.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine

To a solution of5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine*TFA salt(47.75 mg, 0.14 mmol), N-ethyl-N-isopropylpropan-2-amine (50.21 μL, 0.29mmol), and 2-naphthaldehyde (29.26 mg, 0.19 mmol) in 1,2-dichloroethane(0.50 mL) was added NaBH(OAc)₃ (40.00 mg, 0.19 mmol). The mixture wasstirred at 50° C. for 21 h. The reaction mixture was diluted with DCM (5mL) and water (5 mL) and the aqueous layers were extracted into DCM (3×5mL) The combined organic extracts were dried (MgSO₄), filtered, andconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%MeOH/DCM) afforded the title compound (44.1 mg, 86%). ¹H NMR (400 MHz,DMSO-d₆) δ=8.54 (s, 1H), 7.89 (d, J=8.03 Hz, 3H), 7.83 (s, 1H), 7.54 (d,J=8.41 Hz, 1H), 7.45-7.51 (m, 2H), 7.27 (s, 1H), 3.61-3.81 (m, 3H), 3.09(d, J=10.16 Hz, 1H), 2.82 (d, J=10.54 Hz, 1H), 2.60 (s, 3H), 2.44 (t,J=9.79 Hz, 1H), 2.20-2.34 (m, 1H), 2.05 (br s, 1H), 1.63-1.81 (m, 3H);[M+H]=358.2.

Example 2.(3R)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine

The racemic Example 1 (112 mg, 0.31 mmol) was resolved to give the pureenantiomers using a Thar 80 preparative SFC instrument with a Chiralpak®AD-H, 250×30 mm I.D. 5 μm column and eluting with 30% MeOH insupercritical CO₂. Obtained were the two pure enantiomers: The firsteluted compound (title compound, 36.5 mg, 65%, 99.2% ee) was arbitrarilyassigned the (R)-stereoconfiguration. The second eluted compound (40.7mg, 72%, 95.2% ee) was assigned the (S)-stereoconfiguration, Example 3.The purified enantiomers were analyzed using a Shimadzu LC-20ABinstrument with a Chiralpak® AS-H, 150×4.6 mm I.D. 5 μm column andeluting with 10% 2-propanol in hexanes. ¹H NMR (400 MHz, CD₃OD) δ=8.38(s, 1H), 7.77-7.82 (m, 4H), 7.50-7.53 (m, 1H), 7.41-7.44 (m, 2H), 7.20(s, 1H), 3.65-3.85 (m, 3H), 3.15-3.25 (m, 1H), 2.84-2.96 (m, 1H), 2.63(s, 3H), 2.40-2.50 (m, 1H), 2.30-2.39 (m, 1H), 2.04-2.18 (m, 1H),1.70-1.86 (m, 3H); [M+H]=358.2.

Example 3.(3S)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine

The title compound was prepared in a manner analogous to Example 2. ¹HNMR (400 MHz, CD₃OD) δ=8.38 (s, 1H), 7.77-7.82 (m, 4H), 7.50-7.53 (m,1H), 7.41-7.44 (m, 2H), 7.20 (s, 1H), 3.65-3.85 (m, 3H), 3.15-3.25 (m,1H), 2.84-2.96 (m, 1H), 2.63 (s, 3H), 2.40-2.50 (m, 1H), 2.30-2.39 (m,1H), 2.04-2.18 (m, 1H), 1.70-1.86 (m, 3H); [M+H]=358.2.

Example 4.(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(naphthalen-2-yl)methanone

To a solution of5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (21.7 mg,0.10 mmol), DIPEA (80 μL, 0.50 mmol) in DCM (1 mL), was added a solutionof 2-naphthoyl chloride (28.6 mg, 0.15 mmol) in DCM (1 mL) The mixturewas stirred overnight at rt. The reaction was washed with a 10% aq NaOH,dried (K₂CO₃), filtered and concentrated under reduced pressure.Purification (reverse-phase prep-LCMS with a solvent gradient of 5-95%ACN in water with 0.1% added TFA) afforded the title compound. Thecombined pure fractions were concentrated under reduced pressure andneutralized with sat. aq. NaHCO₃, extracted into DCM, dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford the titlecompound (23 mg, 62%). ¹H NMR (400 MHz, CDCl₃) δ=8.00 (s, 1H), 7.84-7.96(m, 3H), 7.58 (dd, J=6.15, 3.14 Hz, 2H), 7.51 (d, J=8.41 Hz, 1H), 3.78(br s, 1H), 3.00-3.69 (m, 2H), 2.73 (br s, 3H), 2.39 (br s, 1H),1.94-2.14 (m, 1H); [M+H]=372.2.

Example 5.(2,3-Dihydro-1H-inden-5-yl)(3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methanone

To a solution of 2,3-dihydro-1H-indene-5-carboxylic acid (42.93 mg, 0.26mmol) in DMF (0.5 mL), was added DIPEA (0.10 mL, 0.57 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (104.52 mg, 0.27 mmol). The mixture was stirredin a sealed vial at rt. After 30 min,5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (55.30 mg,0.25 mmol) in DMF (0.5 mL) was added and the mixture stirred at rt foran additional 16 h. The mixture was diluted with DMF, filtered andpurified (reverse-phase prep-HPLC, 15-60% ACN/H₂O/0.1% TFA) to obtainthe title compound as the TFA salt (56 mg, 40%). ¹H NMR (400 MHz,DMSO-d₆) δ=8.56 (br s, 1H) 6.96-7.53 (m, 4H) 3.91-4.95 (m, 1H) 3.53-3.85(m, 1H) 3.21-3.47 (m, 1H) 2.97-3.20 (m, 1H) 2.88 (br s, 4H) 2.63 (s, 3H)2.13-2.28 (m, 1H) 1.78-2.10 (m, 4H) 1.48-1.75 (m, 2H); [M+H]=362.2.

Example 6.(S)-(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(naphthalen-2-yl)methanone

The racemic Example 4, (101 mg, 0.27 mmol) was resolved to give the pureenantiomers using a Thar 80 preparative SFC instrument with a Chiralpak®AS-H, 250×30 mm I.D. 5 μm column and eluting with 30% MeOH insupercritical CO₂. Obtained were the two pure enantiomers: The firsteluted compound (title compound, 35.5 mg, 70%, >99% ee) was arbitrarilyassigned the (S)-stereoconfiguration. The second eluted compound (36.1mg, 71%, 97.7% ee) was assigned the (R)-stereoconfiguration. Thepurified enantiomers were analyzed using a Shimadzu LC-20AB instrumentwith a Chiralpak® AS-H, 150×4.6 mm I.D. 5 μm column and eluting with 40%ethanol in hexanes. ¹H NMR (400 MHz, CD₃OD) δ=8.40-8.60 (m, 1H),7.80-8.10 (m, 4H), 7.40-7.60 (m, 3H), 7.05-7.25 (m, 1H), 4.60-5.00 (m,1H), 4.20-4.35 (m, 1H), 3.70-3.90 (m, 1H), 3.30-3.50 (m, 1H), 3.10-3.25(m, 1H), 2.55-2.70 (m, 3H), 2.25-2.40 (m, 1H), 1.70-2.20 (m, 3H);[M+H]=372.1.

Example 7.(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(quinolin-4-yl)methanone

To a 1 dram screw cap vial was added quinoline-4-carboxylic acid (0.11mmol), HATU (0.2 mL of a 0.55 M solution in DMF, 0.11 mmol) and DIPEA(20 μL, 0.11 mmol). The mixture was stirred at rt for 30 min then5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (0.109mmol, 0.6 mL of a 0.1817 M solution in DIPEA and DMF) was added. Thevial was sealed and shaken at rt overnight. The mixture was filtered, a5 μL aliquot taken and diluted with 200 μL DMF and an analyticalreverse-phase-UPLC was taken. The desired product mass was observed.Subsequently, based on the retention time of the desired product fromthe analytical UPLC, a corresponding PREP-HPLC gradient was recommendedand the compound was purified. Obtained was the title compound (15 mg,29%) as the TFA salt. [M+H]=373.2.

Example 8.(2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)(quinolin-2-yl)methanone

2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholine (50.00 mg,0.23 mmol) was dissolved in DCM (1.14 mL) DIPEA (79.45 μL, 0.46 mmol)and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (121.04 mg, 0.27 mmol) was added, followed byquinoline-2-carboxylic acid (47.39 mg, 0.27 mmol). The reaction wasstirred at room temperature overnight and then concentrated underreduced pressure. Purification (FCC, SiO₂, 0-5% MeOH/DCM) thenpurification by reverse phase HPLC afforded the title compound as an offwhite solid (41.00 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.25 (m,2H), 8.15-7.99 (m, 2H), 7.88-7.81 (m, 1H), 7.80-7.74 (m, 1H), 7.72-7.66(m, 1H), 7.35-7.23 (m, 1H), 5.45-5.24 (m, 1H), 4.79-4.38 (m, 1H),4.29-4.00 (m, 1H), 3.89 (d, J=11.0 Hz, 1H), 3.50-3.39 (m, 1H), 3.31-3.19(m, 1H), 3.03-2.93 (m, 1H), 2.69-2.57 (m, 3H); [M+H]=375.

Example 9.(3,3-Difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(3-iodo-4-methoxyphenyl)methanone

To a solution of7-(5,5-difluoropiperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine(35 mg, 0.10 mmol) in DCM (0.32 mL) was added TEA (15.94 μl, 0.11 mmol),3-iodo-4-methoxybenzoic acid (26.50 mg, 0.10 mmol), HOBt (17.51 mg, 0.11mmol) and EDCI (21.92 mg, 0.11 mmol). The reaction was stirred at rt for16 h. The crude reaction was filtered and the residue was purified bypreparative reverse phase HPLC to afford the title compound (14 mg,29%). ¹H NMR (400 MHz, CDCl₃) δ=8.58 (s, 1H), 7.95 (d, J=1.96 Hz, 1H),7.50 (dd, J=8.41, 2.15 Hz, 1H), 6.94 (br s, 1H), 6.86 (d, J=8.61 Hz,1H), 4.52-4.85 (m, 1H), 4.03 (br s, 2H), 3.88-3.99 (m, 3H), 3.23-3.58(m, 2H), 2.65-2.76 (m, 5H), [M+H]=514.1.

Example 10.(3R)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

Preparative supercritical fluid chromatography (SFC) was performed usinga 2.1 cm×25 cm (S,S) WhelkO®-1 column from Regis Technologies underisocratic condition using CO₂ with 45% of MeOH as the co-solvent at 70mL per minutes, 100 bar, and 25° C. Elution profiles were monitored atUV. ¹H NMR (400 MHz, CDCl₃) δ=8.50-8.35 (m, 1H), 7.20-6.77 (m, 5H),4.92-4.74 (m, 1H), 4.71-4.55 (m, 1H), 4.44-3.97 (m, 2H), 3.60 (d, J=3.5Hz, 1H), 3.42-2.62 (m, 8H), 2.47-2.24 (m, 1H), 2.10-1.91 (m, 2H), 1.78(d, J=10.2 Hz, 1H); [M+H]=377.7.

Example 11.7-(1-(3-Bromobenzyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

To 5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidinehydrochloride (136 mg, 0.53 mmol) suspended in a mixture of DCE (1 mL)and MeOH (1 mL) was added DIPEA (280 μL, 1.60 mmol). The suspension wassonicated until the mixture became completely homogeneous. To thissolution was added 3-bromobenzaldehyde (75 μL, 0.64 mmol) followed byNaBH₃CN (321 μL, 1.00 mol/L, 0.32 mmol) in THF. The resulting milkymixture was stirred at rt overnight. After diluting with DCM, thereaction mixture was washed with sat. NaHCO₃ and concentrated.Purification (FCC, SiO₂, 0-5% MeOH/DCM) afforded the title compound as ayellow oil (75.3 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 2H),7.82 (br s, 1H), 7.70 (d, J=8.16 Hz, 1H), 7.55 (d, J=7.28 Hz, 1H),7.41-7.48 (m, 1H), 7.24 (s, 1H), 4.33-4.47 (m, 2H), 3.94 (br s, 1H),3.79 (d, J=11.67 Hz, 1H), 3.53 (d, J=11.67 Hz, 1H), 3.32 (t, J=11.11 Hz,1H), 3.06 (br s, 1H), 2.65 (s, 3H), 1.78-2.25 (m, 4H); [M+H]=386.1,388.1.

Example 12.7-(1-((4′-Chloro-3,5-difluoro-[1,1′-biphenyl]-4-yl)methyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

A mixture consisting of7-(1-(4-Bromo-2,6-difluorobenzyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine(65 mg, 0.15 mmol), Pd(PPh₃)₄ (18 mg, 0.02 mmol),4-chloro-phenyl-boronic acid (48 mg, 0.31 mmol) and K₂CO₃ (54 mg, 0.39mmol) in ethyleneglycol dimethyl ether (1.50 mL), EtOH (0.50 mL) andwater (0.50 mL) was heated employing microwave irradiation at 140° C.for 20 min. The reaction mixture was diluted with EtOAc, washed withwater and concentrated to afford crude material that was purified(reverse-phase prep-HPLC, 20-80% ACN/H₂O/0.1% TFA) to obtain the titlecompound as the trifluoroacetate salt (36 mg, 41%). ¹H NMR (400 MHz,DMSO-d₆) δ=8.61 (s, 1H), 7.84 (d, J=8.53 Hz, 2H), 7.68 (d, J=9.16 Hz,2H), 7.57 (d, J=8.41 Hz, 2H), 7.22 (s, 1H), 4.41 (br s, 2H), 3.50-3.86(m, 3H), 2.86-3.26 (m, 2H), 2.63 (s, 3H), 1.72-2.18 (m, 4H);[M+H]=454.2, 456.2.

Example 13.7-(1-([1,1′-Biphenyl]-4-ylmethyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

To 5-methyl-7-(piperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidinehydrochloride (308.00 mg, 1.21 mmol) suspended in 1,2-dichloroethane(1.20 mL) and MeOH (1.20 mL) was added DIPEA (212 μL, 1.21 mmol) andsonicated until fully dissolved. The solution was diluted to a finalvolume of 3 mL with DCE/MeOH (1:1) to reach a final concentration of0.40 M. To 1 dram screw cap vials containing triazolo[1,5-a]pyrimidinesolution (250 μL, 0.1 mmol) and [1,1′-biphenyl]-4-carbaldehyde (20 mg,0.11 mmol) dissolved in DCE/MeOH (110 μL) were added, AcOH (58 μL, 0.1mmol) and NaBH₃CN (100 μL, 1.00 mol/L) dissolved in THF. The vialcontaining the resultant milky mixture was sealed and shaken at rtovernight. After the required time, the reaction vial was diluted with200 μL of DCE/MeOH (1:1), filtered through a 100 mg SiO₂ filter platewetted with 200 μL of DCE/MeOH (1:1) and eluted with an additional 200μL of DCE/MeOH (1:1). The solutions were quality controlled afterfiltration to ensure product elution and the reaction vials containingmaterial concentrated under reduced pressure. Based on the retentiontime of the desired product from the analytical UPLC, a correspondingPREP-HPLC gradient was recommended and the compound purified.

Examples 14-39 were prepared in a manner analogous to Example 12, withthe appropriate starting material and reagent substitutions.

Example 14.1-{[4-(3-Chlorophenyl)-2,6-difluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.90 (s, 1H), 7.69-7.81 (m,3H), 7.51-7.58 (m, 2H), 7.21 (s, 1H), 4.41 (br s, 2H), 3.72-4.05 (m,2H), 3.32-3.65 (m, 2H), 3.12 (br s, 1H), 2.64 (s, 3H), 1.77-2.18 (m,4H); [M+H]=454.2.

Example 15.1-{[4-(2-Chlorophenyl)-2,6-difluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 7.60-7.65 (m, 1H), 7.45-7.52(m, 3H), 7.40 (d, J=8.41 Hz, 2H), 7.23 (s, 1H), 3.72-4.66 (m, 4H), 3.51(br s, 2H), 3.15 (br s, 1H), 2.64 (s, 3H), 1.78-2.19 (m, 4H);[M+H]=454.2.

Example 16.1-{[4-(4-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.60 (s, 1H), 7.70-7.85 (m, 4H), 7.62 (d,J=8.03 Hz, 2H), 7.55 (d, J=8.41 Hz, 2H), 7.23 (s, 1H), 4.42 (br s, 2H),3.94 (br s, 1H), 3.50-3.86 (m, 2H), 3.32 (br s, 1H), 3.05 (br s, 1H),2.63 (s, 3H), 2.01-2.20 (m, 2H), 1.87 (br s, 2H); [M+H]=418.2.

Example 17.1-{[4-(3-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.02 (br s, 1H), 8.62 (s, 1H), 7.85 (d,J=7.91 Hz, 2H), 7.79 (s, 1H), 7.70 (d, J=7.65 Hz, 1H), 7.65 (d, J=8.03Hz, 2H), 7.46-7.57 (m, 2H), 7.25 (s, 1H), 4.44 (br s, 2H), 3.71-4.09 (m,2H), 3.57 (d, J=9.79 Hz, 1H), 3.35 (d, J=11.17 Hz, 1H), 3.07 (br s, 1H),2.65 (s, 3H), 1.79-2.22 (m, 4H); [M+H]=418.2.

Example 18.1-{[4-(2-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.04 (br s, 1H), 8.61 (s, 1H), 7.53-7.69(m, 5H), 7.40-7.50 (m, 3H), 7.26 (s, 1H), 4.46 (br s, 2H), 3.96 (br s,1H), 3.85 (d, J=11.80 Hz, 1H), 3.58 (d, J=11.42 Hz, 1H), 3.36 (br s,1H), 3.10 (br s, 1H), 2.66 (s, 3H), 1.78-2.25 (m, 4H); [M+H]=418.2.

Example 19.1-{[4-(2-Chloro-4-fluorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.00 (br s, 1H), 8.57-8.70 (m, 1H),7.59-7.67 (m, 3H), 7.53-7.59 (m, 2H), 7.48 (dd, J=6.34, 8.47 Hz, 1H),7.36 (dt, J=2.51, 8.47 Hz, 1H), 7.26 (s, 1H), 4.45 (br s, 2H), 3.94 (d,J=11.17 Hz, 2H), 3.58 (d, J=12.05 Hz, 1H), 3.36 (d, J=9.41 Hz, 1H), 3.09(br s, 1H), 2.62-2.70 (m, 3H), 1.81-2.24 (m, 4H); [M+H]=436.2.

Example 20.1-{[4-(4-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.16 (br s, 1H), 8.62 (s, 1H), 7.81 (d,J=8.41 Hz, 2H), 7.67-7.77 (m, 3H), 7.58 (d, J=8.41 Hz, 2H), 7.23 (s,1H), 4.47 (br s, 2H), 3.75-4.14 (m, 2H), 3.58 (br s, 1H), 3.41 (br s,1H), 3.12 (br s, 1H), 2.65 (s, 3H), 1.76-2.23 (m, 4H); [M+H]=436.2.

Example 21.1-{[4-(3-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.17 (br s, 1H), 8.63 (s, 1H), 7.86 (s,1H), 7.69-7.82 (m, 4H), 7.49-7.58 (m, 2H), 7.24 (s, 1H), 4.47 (br s,2H), 3.98 (br s, 1H), 3.84 (br s, 1H), 3.57 (br s, 1H), 3.42 (br s, 1H),3.13 (br s, 1H), 2.65 (s, 3H), 1.78-2.22 (m, 4H); [M+H]=436.2.

Example 22.1-{[4-(2-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.22 (br s, 1H), 8.62 (s, 1H), 7.74 (t,J=7.65 Hz, 1H), 7.59-7.66 (m, 1H), 7.40-7.53 (m, 5H), 7.25 (s, 1H), 4.49(br s, 2H), 3.77-4.09 (m, 2H), 3.33-3.71 (m, 2H), 3.17 (br s, 1H), 2.66(s, 3H), 1.84-2.21 (m, 4H); [M+H]=436.2.

Example 23.4-{3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=10.10 (br s, 1H), 8.61 (s, 1H), 7.98 (d,J=5.14 Hz, 1H), 7.87 (br s, 1H), 7.73 (d, J=8.41 Hz, 2H), 7.59 (d,J=8.41 Hz, 2H), 7.46 (t, J=8.97 Hz, 1H), 7.24 (s, 1H), 4.49 (br s, 2H),3.71-4.09 (m, 2H), 3.58 (br s, 1H), 3.44 (br s, 1H), 3.16 (br s, 1H),2.65 (s, 3H), 1.78-2.23 (m, 4H); [M+H]=403.2.

Example 24.1-{[5-(2-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.19 (br s, 1H), 8.59 (s, 1H), 7.72 (d,J=6.27 Hz, 1H), 7.55-7.68 (m, 2H), 7.40-7.52 (m, 4H), 7.22 (s, 1H), 4.47(br s, 2H), 3.95 (br s, 1H), 3.84 (br s, 1H), 3.57 (br s, 1H), 3.38 (brs, 1H), 3.13 (br s, 1H), 2.64 (s, 3H), 1.79-2.19 (m, 4H); [M+H]=436.2.

Example 25.1-{[5-(2-Chloro-4-fluorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=9.96-10.24 (br s, 1H), 8.59 (s, 1H), 7.70(d, J=7.03 Hz, 1H), 7.61 (dd, J=2.45, 8.85 Hz, 2H), 7.42-7.54 (m, 2H),7.37 (dt, J=2.38, 8.47 Hz, 1H), 7.22 (s, 1H), 4.47 (br s, 2H), 3.71-4.09(m, 2H), 3.58 (br s, 1H), 3.38 (br s, 1H), 3.12 (br s, 1H), 2.64 (s,3H), 1.77-2.20 (m, 4H); [M+H]=454.2.

Example 26.3-{4-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=8.98 (d, J=1.76 Hz, 1H), 8.51-8.76 (m, 2H),8.20 (d, J=7.91 Hz, 1H), 8.06 (d, J=6.02 Hz, 1H), 7.92-8.00 (m, 1H),7.63 (dd, J=4.89, 7.91 Hz, 1H), 7.52 (t, J=9.10 Hz, 1H), 7.24 (s, 1H),4.51 (br s, 2H), 3.82-4.06 (m, 2H), 3.58 (br s, 1H), 3.46 (br s, 1H),3.17 (br s, 1H), 2.62-2.70 (m, 3H), 1.81-2.23 (m, 4H); [M+H]=403.2.

Example 27.4-{4-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=8.85 (d, J=5.90 Hz, 2H), 8.59 (s, 1H), 8.22(d, J=5.27 Hz, 1H), 8.08-8.15 (m, 1H), 8.00 (d, J=5.77 Hz, 2H), 7.57 (t,J=9.10 Hz, 1H), 7.24 (s, 1H), 4.52 (br s, 2H), 3.99 (br s, 1H), 3.86 (brs, 1H), 3.38-3.66 (m, 2H), 3.17 (br s, 1H), 2.65 (s, 3H), 1.80-2.22 (m,4H); [M+H]=403.2.

Example 28.1-{[3-(4-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.06 (br s, 1H), 8.58 (s, 1H), 7.87 (s,1H), 7.78 (d, J=7.53 Hz, 1H), 7.73 (d, J=8.53 Hz, 2H), 7.49-7.62 (m,4H), 7.23 (s, 1H), 4.44 (br s, 2H), 3.94 (br s, 1H), 3.84 (d, J=11.29Hz, 1H), 3.55 (d, J=11.04 Hz, 1H), 3.32 (br s, 1H), 3.07 (br s, 1H),2.63 (s, 3H), 1.79-2.23 (m, 4H); [M+H]=418.2.

Example 29.1-{[3-(3-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.03 (br s, 1H), 8.58 (s, 1H), 7.90 (s,1H), 7.82 (d, J=7.15 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=7.53 Hz, 1H),7.44-7.63 (m, 4H), 7.24 (s, 1H), 4.45 (br s, 2H), 3.94 (br s, 1H), 3.84(d, J=11.04 Hz, 1H), 3.55 (d, J=11.17 Hz, 1H), 3.34 (d, J=7.15 Hz, 1H),3.07 (br s, 1H), 2.63 (s, 3H), 1.78-2.25 (m, 4H); [M+H]=418.2.

Example 30.1-{[3-(2-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.02 (br s, 1H), 8.58 (s, 1H), 7.52-7.64(m, 5H), 7.40-7.47 (m, 3H), 7.23 (s, 1H), 4.44 (d, J=10.79 Hz, 2H), 3.93(br s, 1H), 3.82 (d, J=11.29 Hz, 1H), 3.57 (d, J=10.92 Hz, 1H), 3.31 (d,J=8.91 Hz, 1H), 3.06 (br s, 1H), 2.64 (s, 3H), 1.79-2.21 (m, 4H);[M+H]=418.2.

Example 31.4-{4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=8.83 (d, J=6.02 Hz, 2H), 8.62 (s, 1H),7.97-8.13 (m, 4H), 7.75 (d, J=7.28 Hz, 2H), 7.25 (s, 1H), 4.49 (br s,2H), 3.97 (br s, 1H), 3.81 (d, J=9.91 Hz, 1H), 3.56 (d, J=9.79 Hz, 1H),3.36 (t, J=11.80 Hz, 1H), 3.09 (br s, 1H), 2.65 (s, 3H), 1.80-2.24 (m,4H); [M+H]=385.3.

Example 32.1-{[4-(2-Chloro-4-fluorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.20 (br s, 1H), 8.60 (s, 1H), 7.72 (t,J=7.53 Hz, 1H), 7.62 (dd, J=2.51, 8.78 Hz, 1H), 7.32-7.54 (m, 4H), 7.23(s, 1H), 4.47 (br s, 2H), 3.96 (br s, 1H), 3.84 (br s, 1H), 3.55 (br s,1H), 3.43 (br s, 1H), 3.14 (br s, 1H), 2.64 (s, 3H), 1.78-2.21 (m, 4H);[M+H]=454.2.

Example 33.1-{[5-(4-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.10 (br s, 1H), 8.59 (s, 1H), 7.96 (d,J=5.90 Hz, 1H), 7.85 (br s, 1H), 7.71 (d, J=8.53 Hz, 2H), 7.57 (d,J=8.41 Hz, 2H), 7.45 (t, J=8.97 Hz, 1H), 7.22 (s, 1H), 4.47 (br s, 2H),3.71-4.05 (m, 2H), 3.55 (br s, 1H), 3.42 (br s, 1H), 3.15 (br s, 1H),2.63 (s, 3H), 1.76-2.20 (m, 4H); [M+H]=436.2.

Example 34.1-{[5-(3-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.14 (br s, 1H), 8.59 (s, 1H), 8.01 (d,J=5.65 Hz, 1H), 7.89 (br s, 1H), 7.76 (s, 1H), 7.67 (d, J=7.53 Hz, 1H),7.40-7.58 (m, 3H), 7.23 (s, 1H), 4.47 (br s, 2H), 3.71-4.2 (m, 2H), 3.55(br s, 1H), 3.43 (br s, 1H), 3.14 (br s, 1H), 2.63 (s, 3H), 1.79-2.23(m, 4H); [M+H]=436.2.

Example 35.1-{[3-(2-Chloro-4-fluorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.01 (br s, 1H), 8.59 (s, 1H), 7.46-7.63(m, 6H), 7.36 (dt, J=2.32, 8.38 Hz, 1H), 7.23 (s, 1H), 4.44 (d, J=9.16Hz, 2H), 3.93 (br s, 2H), 3.56 (d, J=11.42 Hz, 1H), 3.30 (d, J=9.41 Hz,1H), 3.06 (br s, 1H), 2.63 (s, 3H), 1.79-2.22 (m, 4H); [M+H]=436.2.

Example 36.3-{3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=9.04 (s, 1H), 8.69 (d, J=4.77 Hz, 1H), 8.63(s, 1H), 8.28 (d, J=8.28 Hz, 1H), 7.85 (d, J=11.04 Hz, 1H), 7.78 (br s,2H), 7.62 (dd, J=4.83, 7.84 Hz, 1H), 7.24 (s, 1H), 4.49 (br s, 2H), 3.99(br s, 1H), 3.85 (d, J=10.54 Hz, 1H), 3.59 (d, J=10.79 Hz, 1H), 3.43 (brs, 1H), 3.15 (br s, 1H), 2.65 (s, 3H), 1.82-2.22 (m, 4H); [M+H]=403.2.

Example 37.7-(1-(2,6-Difluoro-4-(pyridin-3-yl)benzyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ=9.07 (d, J=1.88 Hz, 1H), 8.70 (d, J=4.77 Hz,1H), 8.63 (s, 1H), 8.29 (d, J=8.03 Hz, 1H), 7.80 (d, J=9.03 Hz, 2H),7.61 (dd, J=4.89, 7.91 Hz, 1H), 7.23 (s, 1H), 4.46 (br s, 2H), 4.00 (brs, 1H), 3.84 (br s, 1H), 3.40-3.66 (m, 2H), 3.09-3.22 (m, 1H), 2.65 (s,3H), 1.78-2.18 (m, 4H); [M+H]=421.2.

Example 38.3-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=10.21 (br s, 1H), 9.02 (s, 1H), 8.71 (d,J=4.77 Hz, 1H), 8.60 (s, 1H), 8.28 (d, J=7.78 Hz, 1H), 7.96 (s, 1H),7.89 (d, J=6.78 Hz, 1H), 7.58-7.74 (m, 3H), 7.26 (s, 1H), 4.48 (br s,2H), 3.97 (br s, 1H), 3.87 (d, J=10.29 Hz, 1H), 3.58 (d, J=11.67 Hz,1H), 3.37 (t, J=10.92 Hz, 1H), 3.10 (br s, 1H), 2.64 (s, 3H), 1.80-2.24(m, 4H); [M+H]=385.2.

Example 39.4-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

¹H NMR (400 MHz, DMSO-d₆) δ=10.30 (br s, 1H), 8.85 (d, J=5.77 Hz, 2H),8.60 (s, 1H), 8.09 (br s, 1H), 8.02 (d, J=6.02 Hz, 3H), 7.60-7.82 (m,2H), 7.25 (s, 1H), 4.50 (br s, 2H), 3.97 (br s, 1H), 3.86 (d, J=9.91 Hz,1H), 3.57 (d, J=10.79 Hz, 1H), 3.36 (t, J=11.61 Hz, 1H), 3.10 (br s,1H), 2.64 (s, 3H), 1.81-2.24 (m, 4H); [M+H]=385.3.

Examples 40-131 were prepared in a manner analogous to Example 13, withthe appropriate starting material and reagent substitutions.

Example 40.1-[(3,4-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=368.2.

Example 41.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-1-ylmethyl)piperidine

[M+H]=358.2.

Example 42.1-[(4-Chloro-2-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.1.

Example 43.4-{4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}morpholine

[M+H]=393.2.

Example 44.1-{[4-Fluoro-3-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=394.1.

Example 45.1-{[3-(Furan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 46.1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole

[M+H]=361.2.

Example 47.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(piperidin-1-yl)phenyl]methyl}piperidine

[M+H]=391.1.

Example 48.3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=309.1.

Example 49.2-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine

[M+H]=385.2.

Example 50.4-{2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}morpholine

[M+H]=393.2.

Example 51.3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=327.2.

Example 52.2,6-Dimethyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=337.2.

Example 53.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=309.1.

Example 54.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=309.1.

Example 55.1-[(2,4-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=376.1, 378.1.

Example 56.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1H-pyrrol-1-yl)phenyl]methyl}piperidine

[M+H]=373.2.

Example 57.1-(1-Benzothiophen-2-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=364.1.

Example 58.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(1-phenyl-1H-pyrazol-4-yl)methyl]piperidine

[M+H]=374.2.

Example 59.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(pyrrolidin-1-yl)phenyl]methyl}piperidine

[M+H]=377.2.

Example 60.1-[(2,5-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=376.1, 378.1.

Example 61.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(1H-pyrazol-1-yl)phenyl]methyl}piperidine

[M+H]=374.2.

Example 62.1-[(4-Chloro-2-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=372.1.

Example 63.1-[(3-Methoxy-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=352.2.

Example 64.1-[(2,4-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=368.2.

Example 65.1-(2H-1,3-Benzodioxol-4-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=352.2.

Example 66.1-[(2,6-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=376.1, 378.1.

Example 67.1-{[2-(1H-Imidazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 68.1-[(4-Chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=342.1.

Example 69.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline

[M+H]=359.2.

Example 70.1-[(2-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=338.2.

Example 71.1-[(4-Chloro-2,6-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=378.1.

Example 72.1-[(2,5-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=368.2.

Example 73.1-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 74.1-[(2-Chloro-6-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.1.

Example 75.1-[(2-Chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=342.1.

Example 76.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(4-methylphenyl)methyl]piperidine

[M+H]=322.2.

Example 77.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(1H-pyrazol-1-yl)phenyl]methyl}piperidine

[M+H]=374.2.

Example 78.1-Benzyl-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=308.2.

Example 79.1-[(3-Chloro-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=360.1.

Example 80.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yloxy)phenyl]methyl}piperidine

[M+H]=366.2

Example 81.1-[(2-Fluoro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.2.

Example 82.1-[(4-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=326.2.

Example 83.1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=360.1.

Example 84.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yl)phenyl]methyl}piperidine

[M+H]=350.2.

Example 85.1-[(4-Methoxy-2-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=352.2.

Example 86.1-[(3-Chloro-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=372.2.

Example 87.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole

[M+H]=347.2.

Example 88.1-[(3-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=338.2.

Example 89.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-methylphenyl)methyl]piperidine

[M+H]=322.2.

Example 90.N,N-Dimethyl-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]aniline

[M+H]=351.2.

Example 91.1-[(3,4-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=344.2.

Example 92.1-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=394.1.

Example 93.1-[(3,4-Dimethylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=336.2.

Example 94.1-[(4-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=338.2.

Example 95.1-[(3-Fluoro-5-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

[M+H]=340.2.

Example 96.1-{[2-Methoxy-5-(propan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=380.2.

Example 97.1-(2H-1,3-Benzodioxol-5-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

[M+H]=352.2.

Example 98.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenylphenyl)methyl]piperidine

[M+H]=384.2.

Example 99.3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole

[M+H]=347.2.

Example 100.1-{[4-(Difluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 101.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3-methylphenyl)methyl]piperidine

[M+H]=322.2.

Example 102.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(trifluoromethyl)phenyl]methyl}piperidine

[M+H]=376.2.

Example 103.1-[(2-Fluoro-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.2.

Example 104.1-(1-Benzofuran-2-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=348.2.

Example 105.1-[(2,5-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=344.2.

Example 106.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethyl)phenyl]methyl}piperidine

[M+H]=376.2.

Example 107.1-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-1,3-benzodiazole

[M+H]=362.2.

Example 108.5-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole

[M+H]=365.2.

Example 109.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenyl-1,3-thiazol-5-yl)methyl]piperidine

[M+H]=391.1.

Example 110.1-[(3-Chloro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.1.

Example 111.1-[(2-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=326.2.

Example 112.1-(1-Benzofuran-3-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=348.2.

Example 113.1-[(3-Chloro-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=360.1.

Example 114.1-[(3-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=326.2.

Example 115.1-[(2,3-Dimethylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=336.2.

Example 116.1-(1-Benzothiophen-3-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=364.1.

Example 117.1-[(4-Fluoro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.2.

Example 118.1-[(4-Chloro-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=360.1.

Example 119.1-({3,6-Dimethylimidazo[2,1-b][1,3]thiazol-5-yl}methyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=382.2.

Example 120.7-(1-((6-Methoxynaphthalen-2-yl)methyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

[M+H]=388.2.

Example 121.1-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=388.1.

Example 122.1-{[3,5-Dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=368.2.

Example 123.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[1-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]methyl}piperidine

[M+H]=380.1.

Example 124.2-Methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=323.2.

Example 125.1-{[4-(Furan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 126.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(propan-2-yloxy)phenyl]methyl}piperidine

[M+H]=366.2.

Example 127.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline

[M+H]=359.2.

Example 128.1-{[3-(Difluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 129.1-{[4-(1H-Imidazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.2.

Example 130.5-Chloro-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=343.1.

Example 131.3-Chloro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

[M+H]=343.1.

Examples 132-141 were prepared in a manner analogous to Example 11, withthe appropriate starting material and reagent substitutions.

Example 132.1-[(4-Bromo-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.39 (m, 1H), 7.55-7.46 (m, 1H),7.46-7.38 (m, 1H), 7.38-7.28 (m, 1H), 6.96-6.86 (m, 1H), 4.37-4.23 (m,2H), 4.08-3.93 (m, 2H), 3.80-3.66 (m, 2H), 3.02-2.83 (m, 1H), 2.70 (s,3H), 2.52-2.35 (m, 1H), 2.33-2.20 (m, 1H), 2.18-2.03 (m, 2H);[M+H]=404.1.

Example 133.(3R)-1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.54-8.38 (m, 1H), 7.65-7.50 (m, 2H),7.37-7.27 (m, 2H), 6.93 (s, 1H), 4.37-4.14 (m, 2H), 4.07-3.88 (m, 1H),3.69 (br s, 3H), 2.97-2.79 (m, 1H), 2.75-2.61 (m, 3H), 2.49-2.35 (m,1H), 2.27-1.99 (m, 4H); [M+H]=388.1.

Example 134.(3S)-1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.37 (m, 1H), 7.63-7.47 (m, 2H),7.36-7.27 (m, 2H), 6.93 (s, 1H), 4.37-4.16 (m, 2H), 4.06-3.90 (m, 1H),3.69 (br s, 3H), 2.98-2.80 (m, 1H), 2.76-2.62 (m, 3H), 2.58-2.33 (m,1H), 2.17 (s, 4H); [M+H]=388.1.

Example 135.5-bromo-2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ=8.83-8.73 (m, 1H), 8.54-8.46 (m, 1H),8.13-8.05 (m, 1H), 7.50-7.38 (m, 1H), 7.24-7.14 (m, 1H), 4.70-4.65 (m,1H), 4.63-4.49 (m, 2H), 4.19-3.97 (m, 2H), 3.78-3.64 (m, 1H), 3.53-3.40(m, 1H), 2.69 (s, 3H), 2.40-2.27 (m, 1H), 2.25-1.96 (m, 3H);[M+H]=388.1.

Example 136.5-Bromo-4-methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ=8.79-8.67 (m, 1H), 8.53-8.45 (m, 1H),7.50-7.40 (m, 1H), 7.26-7.12 (m, 1H), 4.60-4.45 (m, 2H), 4.19-3.95 (m,3H), 3.76-3.63 (m, 1H), 3.52-3.40 (m, 1H), 2.69 (s, 3H), 2.45 (s, 3H),2.38-2.28 (m, 1H), 2.21-1.98 (m, 3H); [M+H]=401.1.

Example 137.3-Bromo-2-methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ=8.52-8.47 (m, 1H), 8.07-7.98 (m, 1H),7.30-7.15 (m, 2H), 4.62-4.44 (m, 2H), 4.20-4.05 (m, 2H), 3.79-3.65 (m,2H), 3.48-3.35 (m, 1H), 2.70 (d, J=8.2 Hz, 6H), 2.41-2.25 (m, 1H),2.24-1.97 (m, 3H); [M+H]=401.1.

Example 138.5-Bromo-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyrimidine

¹H NMR (400 MHz, CDCl₃) δ=8.88-8.76 (m, 2H), 8.46-8.37 (m, 1H),7.00-6.90 (m, 1H), 4.59-4.42 (m, 2H), 4.01-3.83 (m, 2H), 3.77-3.58 (m,1H), 3.21-3.06 (m, 1H), 2.69 (s, 3H), 2.48-2.30 (m, 2H), 2.23-2.03 (m,2H), 1.33-1.17 (m, 2H); [M+H]=388.1.

Example 139.1-[(4-Bromo-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.41 (m, 1H), 7.68-7.56 (m, 1H),7.23-7.12 (m, 1H), 6.99-6.87 (m, 1H), 4.32-4.13 (m, 2H), 4.10-3.94 (m,1H), 3.78-3.57 (m, 4H), 2.96-2.78 (m, 2H), 2.69 (s, 3H), 2.59-2.38 (m,1H), 2.37-2.20 (m, 1H), 2.17-2.00 (m, 2H); [M+H]=406.1.

Example 140.(3R)-1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.42 (m, 1H), 7.53-7.42 (m, 1H), 7.26 (s,2H), 7.00-6.90 (m, 1H), 4.35-4.15 (m, 2H), 4.09-3.94 (m, 1H), 3.79-3.62(m, 4H), 2.95-2.85 (m, 1H), 2.69 (s, 3H), 2.55-2.38 (m, 1H), 2.34-2.19(m, 1H), 2.17-1.99 (m, 1H); [M+H]=360.1.

Example 141.(3S)-1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.42 (m, 1H), 7.53-7.42 (m, 1H), 7.26 (s,2H), 7.00-6.90 (m, 1H), 4.35-4.15 (m, 2H), 4.09-3.94 (m, 1H), 3.79-3.62(m, 4H), 2.95-2.85 (m, 1H), 2.69 (s, 3H), 2.55-2.38 (m, 1H), 2.34-2.19(m, 1H), 2.17-1.99 (m, 1H); [M+H]=360.1.

Examples 142-206 were prepared in a manner analogous to Example 1, withthe appropriate starting material and reagent substitutions.

Example 142.1-(2,3-Dihydro-1H-inden-5-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=1.58-1.75 (m, 3H), 1.95-2.08 (m, 3H), 2.21(br s, 1H), 2.38 (t, J=10.16 Hz, 1H), 2.61 (s, 3H), 2.70-2.78 (m, 1H),2.83 (q, J=7.32 Hz, 4H), 3.02 (d, J=9.91 Hz, 1H), 3.43-3.57 (m, 2H),3.60-3.70 (m, 1H), 7.07 (d, J=7.53 Hz, 1H), 7.14-7.20 (m, 2H), 7.28 (s,1H), 8.55 (s, 1H); [M+H]=348.3.

Example 143.1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.40 (s, 1H), 7.46 (d, J=8.28 Hz, 2H), 7.25(d, J=8.03 Hz, 2H), 6.96 (s, 1H), 3.79 (br s, 1H), 3.45-3.63 (m, 2H),3.07 (d, J=10.42 Hz, 1H), 2.77 (br s, 1H), 2.68 (s, 4H), 2.44 (br s,1H), 2.31 (br s, 1H), 2.15 (dd, J=4.08, 12.11 Hz, 1H), 1.68-1.82 (m,3H); [M+H]=386.1, 388.1.

Example 144.1-[(4-Bromo-2,6-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.40 (s, 1H), 7.18 (br s, 1H), 7.10-7.16 (m,3H), 3.79 (br s, 1H), 3.70 (s, 2H), 3.01 (d, J=10.54 Hz, 1H), 2.68 (s,5H), 2.51 (d, J=5.02 Hz, 1H), 1.95-2.14 (m, 1H), 1.66-1.84 (m, 3H);[M+H]=422.1, 424.1.

Example 145.1-[(5-Bromo-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.41 (s, 1H), 7.60 (d, J=5.14 Hz, 1H),7.34-7.40 (m, 1H), 7.09 (br s, 1H), 6.95 (t, J=9.10 Hz, 1H), 3.82 (br s,1H), 3.62 (s, 2H), 3.00-3.13 (m, 1H), 2.70 (m, 4H), 2.52-2.64 (m, 1H),2.47 (br s, 1H), 2.10 (d, J=6.90 Hz, 1H), 1.77 (br s, 3H); [M+H]=404.1,406.1.

Example 146.1-Ethyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole

¹H NMR (400 MHz, DMSO-d₆) δ=10.17 (br s, 1H), 8.54-8.65 (m, 1H), 7.69(s, 1H), 7.63 (d, J=8.03 Hz, 1H), 7.52 (d, J=2.89 Hz, 1H), 7.24 (s, 1H),7.16 (d, J=8.03 Hz, 1H), 6.49 (d, J=2.89 Hz, 1H), 4.48 (br s, 2H), 4.23(q, J=7.15 Hz, 2H), 3.97 (t, J=11.86 Hz, 1H), 3.83 (d, J=11.04 Hz, 1H),3.56 (d, J=11.80 Hz, 1H), 3.25-3.43 (m, 1H), 3.06 (d, J=10.29 Hz, 1H),2.64 (s, 3H), 2.02-2.21 (m, 2H), 1.79-1.99 (m, 2H), 1.39 (t, J=7.15 Hz,3H); [M+H]=375.2.

Example 147.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1,3-thiazol-2-yl)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.30 (br s, 1H), 8.61 (s, 1H), 8.06 (d,J=7.91 Hz, 2H), 7.98 (d, J=3.14 Hz, 1H), 7.86 (d, J=3.14 Hz, 1H), 7.68(d, J=7.91 Hz, 2H), 7.23 (s, 1H), 4.39-4.54 (m, 2H), 3.90-4.02 (m, 1H),3.79 (d, J=10.42 Hz, 1H), 3.57 (d, J=11.54 Hz, 1H), 3.35 (t, J=11.36 Hz,1H), 3.07 (br s, 1H), 2.64 (s, 3H), 1.79-2.23 (m, 4H); [M+H]=391.2.

Example 148.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.39 (br s, 1H), 8.52-8.69 (m, 2H), 7.96(d, J=8.16 Hz, 2H), 7.79 (s, 1H), 7.67 (d, J=8.16 Hz, 2H), 7.24 (s, 1H),6.59 (s, 1H), 4.37-4.52 (m, 2H), 3.90-4.03 (m, 1H), 3.80 (d, J=10.92 Hz,1H), 3.57 (d, J=11.54 Hz, 1H), 3.34 (t, J=11.48 Hz, 1H), 3.08 (d,J=10.16 Hz, 1H), 2.64 (s, 3H), 1.79-2.22 (m, 4H); [M+H]=374.2.

Example 149.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(2-methylpropyl)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.07 (br s, 1H), 8.56 (s, 1H), 7.43 (d,J=7.78 Hz, 2H), 7.20-7.29 (m, 3H), 4.25-4.41 (m, 2H), 3.92 (t, J=11.36Hz, 1H), 3.75 (d, J=10.79 Hz, 1H), 3.50 (d, J=11.92 Hz, 1H), 3.28 (d,J=6.90 Hz, 1H), 3.02 (br s, 1H), 2.63 (s, 3H), 2.47 (d, J=7.15 Hz, 2H),1.75-2.19 (m, 5H), 0.85 (d, J=6.53 Hz, 6H); [M+H]=364.2.

Example 150.1-[(4-Bromo-3-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.16 (br s, 1H), 8.61 (s, 1H), 7.78-7.95(m, 2H), 7.43 (d, J=8.16 Hz, 1H), 7.21 (s, 1H), 4.37 (br s, 2H), 3.91(br s, 1H), 3.75 (d, J=9.66 Hz, 1H), 3.51 (d, J=9.41 Hz, 1H), 3.29 (brs, 1H), 3.02 (br s, 1H), 2.63 (s, 3H), 1.77-2.19 (m, 4H); [M+H]=420.1,422.1.

Example 151.1-[(4Cyclopropylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.04 (br s, 1H), 8.60 (s, 1H), 7.38 (d,J=7.91 Hz, 2H), 7.21 (s, 1H), 7.15 (d, J=7.91 Hz, 2H), 4.23-4.39 (m,2H), 3.92 (t, J=11.48 Hz, 1H), 3.73 (d, J=11.29 Hz, 1H), 3.49 (d,J=11.67 Hz, 1H), 3.19-3.34 (m, 1H), 2.99 (br s, 1H), 2.63 (s, 3H),1.75-2.20 (m, 5H), 0.93-1.03 (m, 2H), 0.69 (q, J=4.89 Hz, 2H);[M+H]=348.2.

Example 152.1-[(4-Bromo-2-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 7.90 (s, 1H), 7.60-7.81 (m,2H), 7.20 (s, 1H), 4.46 (br s, 2H), 3.96 (br s, 1H), 3.76 (br s, 1H),3.48 (br s, 2H), 3.14 (br s, 1H), 2.63 (s, 3H), 1.76-2.19 (m, 4H);[M+H]=420.1, 422.1.

Example 153.1-[(4-tert-Butylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.00 (br s, 1H), 8.60 (s, 1H), 7.48 (q,J=8.28 Hz, 4H), 7.24 (s, 1H), 4.35 (br s, 2H), 3.94 (t, J=11.36 Hz, 1H),3.78 (d, J=11.54 Hz, 1H), 3.52 (d, J=12.17 Hz, 1H), 3.25-3.40 (m, 1H),3.03 (br s, 1H), 2.65 (s, 3H), 1.79-2.21 (m, 4H), 1.30 (s, 9H);[M+H]=364.3.

Example 154.7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]isoquinoline

¹H NMR (400 MHz, DMSO-d₆) δ=9.49 (br s, 1H), 8.54-8.69 (m, 2H), 8.30 (brs, 1H), 8.17 (br s, 1H), 7.82-8.06 (m, 2H), 7.23 (s, 1H), 4.61 (br s,2H), 3.77-4.01 (m, 2H), 3.57 (br s, 1H), 3.38 (br s, 1H), 3.11 (br s,2H), 2.61-2.70 (m, 3H), 1.81-2.24 (m, 3H); [M+H]=359.2.

Example 155.1-[(2,3-Difluoro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.30-7.38 (m, 1H), 7.19-7.28(m, 2H), 4.44 (br s, 2H), 3.96 (br s, 1H), 3.79 (d, J=9.41 Hz, 1H), 3.55(d, J=10.29 Hz, 1H), 3.39 (d, J=10.92 Hz, 1H), 3.09 (br s, 1H), 2.65 (s,3H), 2.33 (s, 3H), 1.78-2.20 (m, 4H); [M+H]=358.2.

Example 156.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethoxy)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.09 (br s, 1H), 8.60 (s, 1H), 7.69 (d,J=8.28 Hz, 2H), 7.50 (d, J=8.16 Hz, 2H), 7.23 (s, 1H), 4.33-4.54 (m,2H), 3.93 (br s, 1H), 3.78 (d, J=11.17 Hz, 1H), 3.54 (d, J=11.92 Hz,1H), 3.32 (br s, 1H), 3.05 (br s, 1H), 2.65 (s, 3H), 1.78-2.22 (m, 4H);[M+H]=392.2.

Example 157.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(trifluoromethoxy)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.80 (d, J=7.53 Hz, 1H),7.61-7.69 (m, 1H), 7.47-7.58 (m, 2H), 7.21 (s, 1H), 4.47 (br s, 2H),3.99 (br s, 1H), 3.79 (d, J=9.54 Hz, 1H), 3.46 (d, J=10.79 Hz, 2H), 3.14(br s, 1H), 2.65 (s, 3H), 1.81-2.24 (m, 4H); [M+H]=392.2.

Example 158.1-{[2-Methoxy-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.00 (br s, 1H), 8.61 (s, 1H), 7.72 (d,J=8.16 Hz, 1H), 7.42 (br s, 2H), 7.20 (s, 1H), 4.40 (br s, 2H), 3.95 (s,4H), 3.80 (d, J=10.29 Hz, 1H), 3.36-3.57 (m, 2H), 3.09 (br s, 1H), 2.63(s, 3H), 1.74-2.20 (m, 4H); [M+H]=406.2.

Example 159.7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=10.26 (br s, 1H), 9.01 (d, J=4.02 Hz, 1H),8.58 (s, 1H), 8.48 (d, J=8.16 Hz, 1H), 8.27 (s, 1H), 8.12 (d, J=8.41 Hz,1H), 7.77 (d, J=8.16 Hz, 1H), 7.65 (dd, J=4.20, 8.22 Hz, 1H), 7.23 (s,1H), 4.57-4.72 (m, 2H), 3.96 (br s, 1H), 3.83 (d, J=11.17 Hz, 1H), 3.61(d, J=11.92 Hz, 1H), 3.40 (br s, 1H), 3.13 (br s, 1H), 2.64 (s, 3H),1.80-2.20 (m, 4H); [M+H]=359.2.

Example 160.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(thiophen-2-yl)phenyl]methyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.21 (br s, 1H), 8.60 (s, 1H), 7.76 (d,J=7.91 Hz, 2H), 7.53-7.62 (m, 4H), 7.22 (s, 1H), 7.16 (t, J=4.33 Hz,1H), 4.33-4.47 (m, 2H), 3.94 (t, J=11.42 Hz, 1H), 3.78 (d, J=11.04 Hz,1H), 3.55 (d, J=11.92 Hz, 1H), 3.32 (t, J=10.73 Hz, 1H), 3.04 (br s,1H), 2.63 (s, 3H), 1.77-2.21 (m, 4H); [M+H]=390.2.

Example 161.1-[(3-Fluoro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.15 (br s, 1H), 8.62 (s, 1H), 7.33-7.43(m, 2H), 7.27 (d, J=7.53 Hz, 1H), 7.23 (s, 1H), 4.27-4.46 (m, 2H), 3.94(t, J=11.17 Hz, 1H), 3.76 (d, J=11.17 Hz, 1H), 3.52 (d, J=11.67 Hz, 1H),3.29 (t, J=11.36 Hz, 1H), 3.03 (br s, 1H), 2.64 (s, 3H), 2.27 (s, 3H),1.78-2.20 (m, 4H); [M+H]=340.2.

Example 162.1-[(2-Chloro-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.28 (br s, 1H), 8.61 (s, 1H), 7.80 (t,J=7.15 Hz, 1H), 7.62 (dd, J=2.38, 8.78 Hz, 1H), 7.39 (dt, J=2.38, 8.41Hz, 1H), 7.21 (s, 1H), 4.49 (br s, 2H), 3.97 (br s, 1H), 3.80 (d, J=9.29Hz, 1H), 3.43-3.59 (m, 2H), 3.19 (d, J=10.54 Hz, 1H), 2.63 (s, 3H),1.77-2.20 (m, 4H); [M+H]=360.1.

Example 163.1-{[2-Methyl-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.01 (br s, 1H), 8.60 (s, 1H), 7.64-7.80(m, 3H), 7.21 (s, 1H), 4.48 (br s, 2H), 3.91-4.03 (m, 1H), 3.78 (d,J=10.54 Hz, 1H), 3.53 (br s, 2H), 3.20 (br s, 1H), 2.64 (s, 3H),1.77-2.21 (m, 4H); [M+H]=390.2.

Example 164.1-{[4-Chloro-3-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 8.11 (br s, 1H), 7.86 (s, 2H),7.23 (s, 1H), 4.51 (br s, 2H), 3.94 (br s, 1H), 3.80 (d, J=8.53 Hz, 1H),3.54 (d, J=10.42 Hz, 1H), 3.37 (t, J=11.73 Hz, 1H), 3.09 (br s, 1H),2.64 (s, 3H), 1.78-2.24 (m, 4H); [M+H]=410.1.

Example 165.1-[(4-Chloro-3-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.52 (d, J=8.03 Hz, 2H), 7.39(d, J=7.91 Hz, 1H), 7.23 (s, 1H), 4.36 (br s, 2H), 3.95 (br s, 1H), 3.77(d, J=10.92 Hz, 1H), 3.53 (d, J=11.67 Hz, 1H), 3.33 (t, J=11.61 Hz, 1H),2.97-3.13 (m, 1H), 2.64 (s, 3H), 2.35 (s, 3H), 1.78-2.22 (m, 4H);[M+H]=356.1.

Example 166.1-[(3,4-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.63 (s, 1H), 7.87 (br s, 1H), 7.77 (d,J=8.16 Hz, 1H), 7.54 (d, J=8.03 Hz, 1H), 7.23 (s, 1H), 4.32-4.49 (m,2H), 3.94 (br s, 1H), 3.78 (d, J=10.92 Hz, 1H), 3.54 (d, J=11.17 Hz,1H), 3.32 (t, J=11.29 Hz, 1H), 3.05 (br s, 1H), 2.64 (s, 3H), 1.78-2.24(m, 4H); [M+H]=376.1, 378.1.

Example 167.1-[(4-Chloro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.53 (d, J=8.03 Hz, 1H), 7.36(s, 1H), 7.23 (s, 1H), 7.12 (d, J=7.91 Hz, 1H), 4.39 (br s, 2H),3.86-4.04 (m, 4H), 3.79 (d, J=11.17 Hz, 1H), 3.54 (d, J=11.67 Hz, 1H),3.33 (t, J=11.67 Hz, 1H), 3.05 (br s, 1H), 2.64 (s, 3H), 1.77-2.23 (m,4H); [M+H]=372.2.

Example 168.1-[(3-Bromo-4-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.19 (br s, 1H), 8.63 (s, 1H), 8.01 (br s,1H), 7.76 (d, J=8.16 Hz, 1H), 7.57 (d, J=7.15 Hz, 1H), 7.23 (s, 1H),4.40 (br s, 2H), 3.93 (br s, 1H), 3.78 (d, J=9.79 Hz, 1H), 3.54 (d,J=11.29 Hz, 1H), 3.31 (t, J=11.48 Hz, 1H), 3.04 (br s, 1H), 2.64 (s,3H), 1.78-2.22 (m, 4H); [M+H]=420.1-424.1.

Example 169.1-[(3-Bromo-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.17 (br s, 1H), 8.62 (s, 1H), 7.82 (s,1H), 7.45 (s, 2H), 7.23 (s, 1H), 4.36 (br s, 2H), 3.94 (br s, 1H), 3.77(d, J=10.67 Hz, 1H), 3.52 (d, J=11.92 Hz, 1H), 3.32 (t, J=11.36 Hz, 1H),3.04 (br s, 1H), 2.64 (s, 3H), 2.38 (s, 3H), 1.78-2.23 (m, 4H);[M+H]=400.1, 402.1.

Example 170.1-[(3-Bromo-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=9.99 (br s, 1H), 8.62 (s, 1H), 7.81 (s, 1H),7.52 (d, J=8.41 Hz, 1H), 7.05-7.31 (m, 2H), 4.33 (br s, 2H), 3.85-3.98(m, 4H), 3.77 (d, J=11.80 Hz, 1H), 3.51 (d, J=11.67 Hz, 1H), 3.28 (d,J=7.15 Hz, 1H), 3.02 (br s, 1H), 2.65 (s, 3H), 1.76-2.22 (m, 4H);[M+H]=416.1, 418.1.

Example 171.1-[(3-Bromo-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.96 (d, J=5.52 Hz, 1H), 7.60(br s, 1H), 7.50 (t, J=8.60 Hz, 1H), 7.24 (s, 1H), 4.40 (br s, 2H), 3.93(br s, 1H), 3.78 (d, J=10.42 Hz, 1H), 3.54 (d, J=11.67 Hz, 1H), 3.32 (t,J=11.54 Hz, 1H), 3.05 (br s, 1H), 2.64 (s, 3H), 1.76-2.23 (m, 4H);[M+H]=404.2, 406.2.

Example 172.1-[(4-Bromo-3-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.21 (br s, 1H), 8.62 (s, 1H), 7.70 (d,J=8.16 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J=7.91 Hz, 1H), 7.23 (s, 1H),4.35 (br s, 2H), 3.88-4.02 (m, 1H), 3.77 (d, J=11.17 Hz, 1H), 3.52 (d,J=12.05 Hz, 1H), 3.32 (t, J=11.80 Hz, 1H), 3.04 (br s, 1H), 2.64 (s,3H), 2.38 (s, 3H), 1.72-2.21 (m, 4H); [M+H]=400.1, 402.1.

Example 173.1-[(4-Iodophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=10.25 (br s, 1H), 8.62 (s, 1H), 7.86 (d,J=8.03 Hz, 2H), 7.34 (d, J=7.78 Hz, 2H), 7.22 (s, 1H), 4.28-4.45 (m,2H), 3.88-4.00 (m, 1H), 3.75 (d, J=11.17 Hz, 1H), 3.53 (d, J=11.80 Hz,1H), 3.31 (t, J=11.73 Hz, 1H), 2.96-3.11 (m, 1H), 2.64 (s, 3H),1.75-2.21 (m, 4H); [M+H]=434.1.

Example 174.(3R)-1-[(4-Bromo-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.35 (m, 1H), 7.70-7.54 (m, 1H), 7.26 (s,2H), 7.19-7.12 (m, 1H), 6.90 (s, 1H), 4.36-4.12 (m, 2H), 4.11-3.91 (m,1H), 3.76-3.56 (m, 3H), 3.00-2.79 (m, 1H), 2.67 (s, 2H), 2.53-2.37 (m,1H), 2.33-2.01 (m, 3H); [M+H]=405.1.

Example 175.3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.40 (m, 1H), 7.86-7.68 (m, 3H),7.65-7.53 (m, 1H), 6.98-6.85 (m, 1H), 4.42-4.24 (m, 2H), 4.10-3.91 (m,1H), 3.78-3.61 (m, 3H), 3.05-2.86 (m, 1H), 2.68 (s, 3H), 2.54-2.36 (m,1H), 2.33-2.01 (m, 3H); [M+H]=333.1.

Example 176.2-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.36 (m, 1H), 7.93-7.81 (m, 1H),7.79-7.67 (m, 1H), 7.37-7.29 (m, 1H), 6.93 (s, 1H), 4.41-4.18 (m, 2H),4.08-3.90 (m, 1H), 3.77-3.62 (m, 3H), 3.02-2.85 (m, 1H), 2.69 (s, 3H),2.57-2.38 (m, 1H), 2.30-2.02 (m, 3H); [M+H]=351.1.

Example 177.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.33 (m, 1H), 7.79-7.68 (m, 2H),7.66-7.55 (m, 2H), 6.98-6.83 (m, 1H), 4.40-4.25 (m, 2H), 4.04-3.94 (m,1H), 3.80-3.62 (m, 3H), 3.01-2.84 (m, 1H), 2.68 (s, 3H), 2.53-2.40 (m,1H), 2.32-2.03 (m, 3H); [M+H]=333.1.

Example 178.1-{[3-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.38 (m, 1H), 7.74-7.61 (m, 1H),7.45-7.34 (m, 2H), 6.96-6.86 (m, 1H), 4.37-4.24 (m, 2H), 4.05-3.94 (m,1H), 3.77-3.62 (m, 3H), 2.99-2.83 (m, 1H), 2.69 (s, 3H), 2.56-2.39 (m,1H), 2.32-2.03 (m, 3H); [M+H]=394.1.

Example 179.(3S)-1-{[3-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.39 (m, 1H), 7.73-7.64 (m, 1H),7.44-7.32 (m, 2H), 6.99-6.82 (m, 1H), 4.39-4.24 (m, 3H), 4.05-3.95 (m,1H), 3.77-3.63 (m, 3H), 2.99-2.86 (m, 1H), 2.69 (s, 2H), 2.55-2.41 (m,1H), 2.33-2.02 (m, 3H); [M+H]=394.3.

Example 180.2-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.36 (m, 1H), 7.71-7.55 (m, 2H),7.46-7.34 (m, 1H), 6.91 (s, 1H), 4.35-4.18 (m, 2H), 4.06-3.89 (m, 1H),3.77-3.55 (m, 3H), 3.03-2.83 (m, 1H), 2.68 (s, 3H), 2.55 (s, 4H), 2.17(s, 3H); [M+H]=347.2.

Example 181.1-{[3-Fluoro-5-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.48-8.37 (m, 1H), 7.61-7.52 (m, 1H),7.49-7.39 (m, 2H), 6.98-6.87 (m, 1H), 4.38-4.27 (m, 2H), 4.04-3.91 (m,1H), 3.80-3.59 (m, 3H), 2.99-2.85 (m, 1H), 2.69 (s, 3H), 2.54-2.38 (m,1H), 2.31-2.04 (m, 3H); [M+H]=394.2.

Example 182.1-[(4-Chloro-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.48-8.37 (m, 1H), 7.30-7.21 (m, 1H),7.19-7.09 (m, 2H), 6.99-6.87 (m, 1H), 4.33-4.16 (m, 2H), 4.04-3.92 (m,1H), 3.75-3.61 (m, 3H), 3.00-2.84 (m, 1H), 2.68 (s, 3H), 2.52-2.34 (m,1H), 2.28-2.05 (m, 3H); [M+H]=378.2.

Example 183.2-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile

¹H NMR (400 MHz, CDCl₃) δ=8.48-8.38 (m, 1H), 7.77-7.66 (m, 1H),7.51-7.36 (m, 2H), 6.98-6.83 (m, 1H), 4.39-4.22 (m, 2H), 4.06-3.92 (m,1H), 3.79-3.57 (m, 4H), 2.94-2.89 (m, 1H), 2.69 (s, 3H), 2.57-2.42 (m,1H), 2.33-2.03 (m, 3H); [M+H]=351.2.

Example 184.(3R)-1-[(4-Chloro-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.32-8.49 (m, 1H), 7.12-7.22 (m, 2H), 6.91 (s,1H), 4.16-4.34 (m, 2H), 3.90-4.06 (m, 1H), 3.52-3.76 (m, 3H), 2.85-3.01(m, 1H), 2.66 (s, 3H), 2.32-2.48 (m, 1H), 2.00-2.32 (m, 3H);[M+H]=378.1.

Example 185.1-[(3,5-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.39-8.49 (m, 1H), 6.99-7.08 (m, 2H),6.85-6.97 (m, 2H), 4.15-4.33 (m, 2H), 3.91-4.07 (m, 1H), 3.56-3.74 (m,4H), 2.81-2.99 (m, 1H), 2.69 (s, 3H), 2.38-2.55 (m, 1H), 2.02-2.32 (m,3H); [M+H]=344.2.

Example 186.(3R)-1-[(4-Bromo-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=2.04-2.32 (m, 3H), 2.34-2.53 (m, 1H), 2.66 (s,2H), 2.68 (s, 2H), 2.86-3.00 (m, 1H), 3.60-3.77 (m, 3H), 3.90-4.05 (m,1H), 4.17-4.34 (m, 2H), 6.86-6.97 (m, 1H), 7.06-7.19 (m, 2H), 8.38-8.50(m, 1H); [M+H]=423.1.

Example 187.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3,4,5-trifluorophenyl)methyl]piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 7.46-7.64 (m, 2H), 7.22 (s,1H), 4.33 (br s, 2H), 3.69-4.01 (m, 2H), 3.21-3.54 (m, 2H), 2.87-3.06(m, 1H), 2.63 (s, 3H), 1.74-2.22 (m, 4H); [M+H]=362.2.

Example 188.1-{[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.59 (s, 1H), 7.64-7.81 (m, 2H), 7.50 (d,J=7.4 Hz, 1H), 7.22 (s, 1H), 4.40 (br s, 2H), 3.63-4.02 (m, 4H), 3.02(br s, 1H), 2.63 (s, 3H), 1.76-2.21 (m, 4H); [M+H]=410.3.

Example 189.1-{[3-Fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 8.24 (t, J=2.5 Hz, 1H), 7.92(t, J=8.2 Hz, 1H), 7.79-7.86 (m, 1H), 7.69 (d, J=12.2 Hz, 1H), 7.51 (d,J=7.7 Hz, 1H), 7.23 (s, 1H), 6.53-6.66 (m, 1H), 4.42 (br s, 2H),3.69-4.04 (m, 4H), 3.23-3.43 (m, 1H), 2.63 (s, 3H), 1.76-2.22 (m, 4H);[M+H]=392.3.

Example 190.(3S)-1-{[3,5-Difluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=9.22-9.22 (m, 1H), 8.44-8.57 (m, 1H),7.40-7.52 (m, 2H), 7.16-7.24 (m, 1H), 4.43-4.54 (m, 2H), 3.98-4.11 (m,1H), 3.87-3.98 (m, 1H), 3.57-3.68 (m, 1H), 3.33-3.43 (m, 1H), 3.07-3.24(m, 1H), 2.71 (s, 2H), 2.26-2.36 (m, 1H), 2.16-2.25 (m, 1H), 1.98-2.14(m, 2H); [M+H]=412.1.

Example 191.(3S)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-[(3,4,5-trifluorophenyl)methyl]piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.53 (s, 1H), 7.27 (dd, J=8.8, 6.8 Hz, 2H),7.22 (s, 1H), 3.59-3.69 (m, 1H), 3.53 (s, 2H), 3.00-3.08 (m, 1H),2.71-2.80 (m, 1H), 2.58 (s, 3H), 2.34 (t, J=10.4 Hz, 1H), 2.13-2.24 (m,1H), 1.99-2.08 (m, 1H), 1.58-1.77 (m, 3H); [M+H]=362.3.

Example 192.3-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ=8.56-8.71 (m, 2H), 8.43-8.54 (m, 1H),7.85-7.97 (m, 1H), 7.15-7.30 (m, 1H), 4.48-4.65 (m, 2H), 3.93-4.15 (m,2H), 3.64-3.76 (m, 1H), 3.34-3.50 (m, 1H), 3.08-3.29 (m, 1H), 2.71 (s,3H), 2.15-2.37 (m, 2H), 1.94-2.15 (m, 2H); [M+H]=327.1.

Example 193.1-[(2-Bromo-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.41-8.53 (m, 1H), 7.72-7.84 (m, 1H),7.11-7.22 (m, 1H), 4.58-4.70 (m, 2H), 3.81-4.07 (m, 2H), 3.54-3.67 (m,1H), 3.32-3.37 (m, 1H), 3.02-3.16 (m, 1H), 2.69 (br s, 3H), 2.12-2.37(m, 2H), 1.94-2.12 (m, 2H); [M+H]=393.1.

Example 194.1-[(2-Methyl-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.37-8.47 (m, 1H), 7.41-7.50 (m, 1H),7.19-7.29 (m, 1H), 3.80 (s, 3H), 3.12-3.24 (m, 1H), 2.78-2.93 (m, 1H),2.60-2.73 (m, 6H), 2.45-2.56 (m, 1H), 2.28-2.40 (m, 1H), 2.07-2.21 (m,1H), 1.67-1.92 (m, 4H); [M+H]=329.2.

Example 195.1-{[2-(4-Fluorophenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.45-8.56 (m, 1H), 7.94-8.07 (m, 3H),7.18-7.32 (m, 3H), 4.71-4.81 (m, 2H), 3.98-4.12 (m, 2H), 3.66-3.80 (m,1H), 3.34-3.46 (m, 1H), 3.11-3.26 (m, 1H), 2.70 (s, 3H), 2.17-2.39 (m,2H), 2.03-2.15 (m, 2H); [M+H]=409.1.

Example 196.1-{[2-(3-Fluorophenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.35-8.62 (m, 1H), 8.03-8.11 (m, 1H),7.67-7.82 (m, 2H), 7.46-7.58 (m, 1H), 7.17-7.34 (m, 2H), 4.74-4.82 (m,2H), 3.99-4.13 (m, 2H), 3.69-3.79 (m, 1H), 3.34-3.45 (m, 1H), 3.14-3.28(m, 1H), 2.70 (s, 3H), 2.20-2.36 (m, 2H), 1.99-2.14 (m, 2H);[M+H]=409.2.

Example 197.1-{[2-(3-Methoxyphenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.39-8.56 (m, 1H), 7.98-8.07 (m, 1H),7.47-7.54 (m, 2H), 7.33-7.45 (m, 1H), 7.14-7.23 (m, 1H), 7.00-7.12 (m,1H), 4.72-4.83 (m, 2H), 3.97-4.13 (m, 2H), 3.86 (s, 3H), 3.66-3.82 (m,1H), 3.34-3.47 (m, 1H), 3.10-3.27 (m, 1H), 2.70 (s, 3H), 2.19-2.38 (m,2H), 2.00-2.14 (m, 2H); [M+H]=421.1.

Example 198.4-{5-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-yl}morpholine

¹H NMR (400 MHz, CD₃OD) δ=8.44-8.57 (m, 1H), 7.33-7.45 (m, 1H),7.09-7.28 (m, 1H), 4.46-4.61 (m, 2H), 3.91-4.10 (m, 2H), 3.72-3.82 (m,4H), 3.63-3.72 (m, 1H), 3.45-3.53 (m, 4H), 3.34-3.39 (m, 1H), 3.07-3.17(m, 1H), 2.70 (s, 3H), 2.16-2.35 (m, 2H), 2.02-2.11 (m, 2H);[M+H]=400.1.

Example 199.1-[(2-Bromo-1,3-thiazol-4-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.45-8.55 (m, 1H), 7.76-7.91 (m, 1H),7.11-7.25 (m, 1H), 4.45-4.63 (m, 2H), 3.97-4.11 (m, 2H), 3.67-3.77 (m,1H), 3.34-3.47 (m, 1H), 3.10-3.28 (m, 1H), 2.70 (s, 3H), 1.98-2.37 (m,5H); [M+H]=393.1.

Example 200.1-[(2-Bromo-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.41-8.61 (m, 1H), 7.67-7.92 (m, 1H),7.10-7.29 (m, 1H), 4.66-4.80 (m, 2H), 3.92-4.11 (m, 2H), 3.61-3.75 (m,1H), 3.33-3.43 (m, 1H), 3.08-3.21 (m, 1H), 2.70 (s, 3H), 2.15-2.38 (m,2H), 1.91-2.14 (m, 2H); [M+H]=393.1.

Example 201.N,N-Dimethyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-amine

¹H NMR (400 MHz, CD₃OD) δ=8.46-8.58 (m, 1H), 7.43-7.51 (m, 1H),7.16-7.24 (m, 1H), 4.47-4.60 (m, 2H), 3.91-4.10 (m, 2H), 3.61-3.73 (m,1H), 3.32-3.41 (m, 1H), 3.21 (s, 7H), 2.70 (s, 3H), 1.96-2.37 (m, 5H);[M+H]=358.2.

Example 202.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl]methyl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.44-8.60 (m, 1H), 7.54-7.65 (m, 1H),7.15-7.23 (m, 1H), 4.48-4.62 (m, 2H), 3.90-4.13 (m, 2H), 3.63-3.72 (m,1H), 3.52-3.62 (m, 4H), 3.34-3.45 (m, 1H), 3.07-3.19 (m, 1H), 2.70 (s,3H), 2.25-2.34 (m, 1H), 2.17 (s, 7H); [M+H]=384.1.

Example 203.1-[(3-Bromo-1,2-oxazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.40-8.56 (m, 1H), 7.15-7.26 (m, 1H),6.87-7.00 (m, 1H), 4.65 (s, 2H), 3.87-4.09 (m, 2H), 3.58-3.67 (m, 1H),3.32-3.42 (m, 1H), 3.09-3.24 (m, 1H), 2.70 (s, 3H), 1.95-2.34 (m, 4H);[M+H]=377.2.

Example 204.1-[(3-Bromo-4,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.52 (s, 1H), 7.82 (dd, J=10.2, 7.8 Hz, 1H),7.56 (dd, J=11.7, 9.0 Hz, 2H), 7.26 (s, 1H), 3.61-3.71 (m, 1H), 3.55 (s,2H), 3.00-3.08 (m, 1H), 2.70-2.80 (m, 1H), 2.58 (s, 3H), 2.49-2.54 (m,1H), 2.28-2.38 (m, 1H), 1.99-2.10 (m, 1H), 1.59-1.76 (m, 3H);[M+H]=422.2.

Example 205.1-[(5-Bromo-4-methyl-1,3-thiazol-2-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.46-8.57 (m, 1H), 7.16-7.25 (m, 1H),4.61-4.76 (m, 2H), 4.00-4.16 (m, 2H), 3.69-3.80 (m, 1H), 3.38-3.49 (m,1H), 3.15-3.28 (m, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 2.26-2.35 (m, 1H),1.95-2.23 (m, 3H); [M+H]=407.1.

Example 206.N,N,4-Trimethyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-amine

¹H NMR (400 MHz, CD₃OD) δ=8.47-8.54 (m, 1H), 7.16-7.25 (m, 1H), 4.52 (s,2H), 3.94-4.11 (m, 2H), 3.65-3.75 (m, 1H), 3.41-3.51 (m, 1H), 3.27 (s,6H), 3.11-3.21 (m, 1H), 2.70 (s, 3H), 2.24-2.39 (m, 4H), 2.17-2.22 (m,1H), 2.02-2.12 (m, 2H); [M+H]=372.1.

Examples 207-289 were prepared in a manner analogous to Example 4, withthe appropriate starting material and reagent substitutions.

Example 207.1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=1.85 (br s, 1H), 1.98-2.15 (m, 1H), 2.40 (d,J=10.54 Hz, 1H), 2.77 (s, 3H), 3.17-3.35 (m, 3H), 3.45 (t, J=11.29 Hz,1H), 3.67-3.83 (m, 1H), 4.58-4.85 (m, 6H), 6.82 (d, J=8.28 Hz, 1H), 6.95(br s, 1H), 7.27 (s, 1H), 7.34 (br s, 1H), 8.54 (br s, 1H); [M+H]=364.4.

Example 208.1-[(3,4-Dihydro-2H-1-benzopyran-6-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=1.95-2.13 (m, 4H), 2.40 (d, J=10.29 Hz, 1H),2.76 (s, 4H), 2.82 (t, J=6.27 Hz, 3H), 3.44 (t, J=11.17 Hz, 1H),3.67-3.82 (m, 1H), 4.13-4.31 (m, 4H), 6.82 (d, J=8.03 Hz, 1H), 6.93 (brs, 1H), 7.15-7.26 (m, 2H), 8.52 (br s, 1H); [M+H]=378.4.

Example 209.4-[(3-Iodophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.42 (m, 1H), 7.84 (d, J=16.8 Hz, 2H),7.55 (br s, 1H), 7.30-7.18 (m, 2H), 4.25-3.86 (m, 2H), 3.77-3.51 (m,3H), 2.61 (d, J=11.0 Hz, 3H), 2.46-2.38 (m, 1H), 2.32-2.14 (m, 1H);[M+H]=450.1.

Example 210.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.42 (m, 1H), 7.84 (d, J=16.8 Hz, 2H),7.55 (br s, 1H), 7.30-7.18 (m, 2H), 4.25-3.86 (m, 2H), 3.77-3.51 (m,3H), 2.61 (d, J=11.0 Hz, 3H), 2.46-2.38 (m, 1H), 2.32-2.14 (m, 1H);[M+H]=374.2.

Example 211.3,3-Difluoro-1-[(3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.77-8.35 (m, 1H), 7.78 (t, J=1.6 Hz, 2H),7.46 (s, 1H), 7.28 (t, J=7.2 Hz, 3H), 4.92-3.31 (m, 5H), 2.59 (br s,5H); [M+H]=484.2.

Example 212.4-[(4-Fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.58 (br s, 1H), 7.70-7.47 (m, 2H),7.35-7.12 (m, 3H), 5.33-3.67 (m, 5H), 3.23-2.78 (m, 2H), 2.70-2.54 (m,3H); [M+H]=342.2.

Example 213.4-Benzoyl-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.40 (m, 1H), 7.52-7.43 (m, 5H),7.33-7.20 (m, 1H), 5.37-3.49 (m, 5H), 3.19-2.80 (m, 2H), 2.63 (s, 3H);[M+H]=324.2.

Example 214.4-[(3-Chloro-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.40 (m, 1H), 7.89-7.65 (m, 1H),7.63-7.36 (m, 2H), 7.31-7.11 (m, 1H), 5.49-3.75 (m, 5H), 3.27-2.70 (m,2H), 2.69-2.56 (m, 3H); [M+H]=376.2.

Example 215.4-[(3-Fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.34 (m, 1H), 7.33 (d, J=8.6 Hz, 5H),5.40-4.87 (m, 2H), 4.52-3.73 (m, 3H), 3.21-2.78 (m, 2H), 2.63 (br s,3H); [M+H]=342.2.

Example 216.4-{[4-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.82-8.24 (m, 1H), 7.92 (br s, 2H), 7.64 (t,J=9.8 Hz, 1H), 7.44-7.12 (m, 1H), 5.42-5.08 (m, 1H), 4.61-3.36 (m, 4H),3.23-2.74 (m, 2H), 2.63 (br s, 3H); [M+H]=410.2.

Example 217.4-[(4-Methoxyphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.60 (s, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.26(s, 1H), 7.07-6.94 (m, 2H), 5.27 (d, J=7.4 Hz, 1H), 5.02-3.80 (m, 4H),3.79 (s, 3H), 3.27-2.82 (m, 2H), 2.63 (s, 3H); [M+H]=354.2.

Example 218.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(4-phenylphenyl)carbonyl]morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.74-8.51 (m, 1H), 7.86-7.19 (m, 10H),5.51-3.40 (m, 5H), 3.14 (d, J=5.1 Hz, 2H), 2.74-2.56 (m, 3H);[M+H]=400.2.

Example 219.4-[(4-Chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.48 (m, 1H), 7.54 (s, 4H), 7.35-7.20(m, 1H), 5.40-3.43 (m, 5H), 3.27-2.71 (m, 2H), 2.63 (s, 3H);[M+H]=358.2.

Example 220.4-[(3-Chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.49-7.51 (m, 1H), 7.46-7.35 (m, 2H), 7.25 (brs, 1H), 7.17-7.08 (m, 1H), 5.66-2.70 (m, 7H), 1.60 (br s, 3H);[M+H]=358.2.

Example 221.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(trifluoromethoxy)phenyl]carbonyl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.27 (m, 1H), 7.65-7.59 (m, 1H),7.59-7.45 (m, 3H), 7.27 (br s, 1H), 5.39-3.95 (m, 4H), 3.52-2.81 (m,3H), 2.63 (br s, 3H); [M+H]=408.2.

Example 222.4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.74-8.38 (m, 1H), 7.74 (t, J=2.0 Hz, 1H),7.66-7.50 (m, 2H), 7.36-7.13 (m, 1H), 5.52-4.92 (m, 1H), 4.54-3.33 (m,4H), 3.20-2.76 (m, 2H), 2.62 (br s, 3H); [M+H]=392.2.

Example 223.4-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ=8.74-8.41 (m, 1H), 7.96 (d, J=7.8 Hz, 2H),7.81-7.58 (m, 2H), 7.42-7.08 (m, 1H), 5.40-5.10 (m, 1H), 4.55-3.35 (m,4H), 3.22-2.77 (m, 2H), 2.67-2.54 (m, 3H); [M+H]=349.2.

Example 224.4-[(3,4-Difluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.84-8.33 (m, 1H), 7.87-7.06 (m, 4H),5.43-5.04 (m, 1H), 4.59-3.44 (m, 3H), 3.22-2.78 (m, 2H), 2.63 (s, 3H);[M+H]=360.2.

Example 225.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-2-yl)carbonyl]piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.22-7.86 (m, 4H), 7.77-7.44 (m, 3H),7.40-7.18 (m, 1H), 5.07-4.74 (m, 1H), 4.70-3.33 (m, 4H), 2.83-2.53 (m,5H); [M+H]=408.3.

Example 226.4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.35 (m, 1H), 7.88-7.13 (m, 5H),5.64-3.34 (m, 6H), 3.17-2.80 (m, 1H), 2.63 (br s, 3H); [M+H]=402.2.

Example 227.3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.36 (m, 1H), 8.18-7.54 (m, 4H),7.40-7.18 (m, 1H), 5.52-3.71 (m, 5H), 3.15 (d, J=5.1 Hz, 2H), 2.62 (brs, 3H); [M+H]=349.3.

Example 228.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(trifluoromethyl)phenyl]carbonyl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.79-8.26 (m, 1H), 8.04-7.66 (m, 4H),7.36-7.14 (m, 1H), 5.50-3.39 (m, 5H), 3.25-2.80 (m, 2H), 2.63 (br s,3H); [M+H]=392.2.

Example 229.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[4-(trifluoromethyl)phenyl]carbonyl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.77-8.29 (m, 1H), 7.85 (d, J=8.2 Hz, 4H),7.42-7.13 (m, 1H), 5.49-3.40 (m, 5H), 3.23-2.68 (m, 2H), 2.71-2.53 (m,3H); [M+H]=392.2.

Example 230.4-[(3-Ethoxyphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.22 (m, 1H), 7.49-7.14 (m, 2H),7.07-6.92 (m, 3H), 5.43-3.33 (m, 8H), 3.25-2.74 (m, 1H), 2.71-2.56 (m,3H), 1.33 (t, J=7.0 Hz, 3H); [M+H]=368.3.

Example 231.4-[(3-bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.45 (m, 1H), 8.12-7.80 (m, 1H),7.66-7.55 (m, 1H), 7.53-7.44 (m, 1H), 7.25 (br s, 1H), 5.46-4.96 (m,1H), 4.01 (d, J=7.0 Hz, 3H), 3.60-3.38 (m, 1H), 3.24-2.75 (m, 2H), 2.63(s, 3H); [M+H]=421.2.

Example 232.1-[(3-Chlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.34 (m, 1H), 7.52 (s, 5H), 5.00-4.55(m, 1H), 4.49-3.31 (m, 4H), 2.59 (m, 5H); [M+H]=392.2.

Example 233.1-[(3,5-Dichlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.36 (m, 1H), 7.91-7.71 (m, 1H), 7.51(d, J=2.0 Hz, 2H), 7.35-7.20 (m, 1H), 4.93-4.66 (m, 1H), 4.14-3.65 (m,2H), 3.51-3.33 (m, 1H), 2.81-2.51 (m, 6H); [M+H]=426.2.

Example 234.1-[(3-Bromophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.74-8.31 (m, 1H), 7.72-7.61 (m, 2H),7.49-7.40 (m, 2H), 7.36-7.19 (m, 1H), 5.12-4.51 (m, 1H), 4.24-3.65 (m,3H), 2.59 (br s, 6H); [M+H]=437.2.

Example 235.1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.57 (br s, 1H), 7.82 (dd, J=6.7, 2.0 Hz,1H), 7.43-7.61 (m, 2H), 7.27 (br s, 1H), 4.77 (br s, 1H), 4.02-4.26 (m,1H), 3.59-3.97 (m, 2H), 3.32-3.52 (m, 1H), 2.53-2.81 (m, 5H);[M+H]=454.2.

Example 236.3-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.36 (m, 1H), 8.06-7.93 (m, 2H),7.83-7.65 (m, 2H), 7.42-7.07 (m, 1H), 4.94-4.61 (m, 1H), 4.18-3.74 (m,3H), 2.59 (br s, 6H); [M+H]=383.2.

Example 237.3,3-Difluoro-1-{[4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.35 (m, 1H), 7.86-7.81 (m, 2H),7.68-7.62 (m, 1H), 7.35-7.21 (m, 1H), 4.96-4.61 (m, 1H), 4.17-3.77 (m,3H), 2.70-2.58 (m, 6H); [M+H]=444.3.

Example 238.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(trifluoromethyl)phenyl]carbonyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.30 (m, 1H), 7.89-7.74 (m, 4H),7.37-7.15 (m, 1H), 5.06-4.71 (m, 1H), 4.19-3.76 (m, 3H), 2.75-2.57 (m,6H); [M+H]=426.2.

Example 239.1-[(3-Chloro-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.67-8.47 (m, 1H), 7.74-7.71 (m, 1H),7.55-7.50 (m, 2H), 7.36-7.15 (m, 1H), 4.93-4.65 (m, 1H), 4.23-3.68 (m,3H), 2.75-2.53 (m, 6H); [M+H]=410.2.

Example 240.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethyl)phenyl]carbonyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.44 (m, 1H), 7.89-7.82 (m, 2H),7.70-7.66 (m, 2H), 7.41-7.13 (m, 1H), 5.01-4.75 (m, 1H), 4.17-3.71 (m,3H), 2.78-2.57 (m, 6H); [M+H]=426.2.

Example 241.(2R)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.24 (m, 1H), 8.21-7.85 (m, 4H),7.68-7.47 (m, 3H), 7.28 (br s, 1H), 5.54-3.48 (m, 5H), 3.24-2.77 (m,2H), 2.63 (br s, 3H); [M+H]=374.3.

Example 242.(2S)-2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.27 (m, 1H), 8.24-7.89 (m, 4H),7.73-7.53 (m, 3H), 7.28 (br s, 1H), 5.64-3.51 (m, 5H), 3.21-2.71 (m,2H), 2.63 (br s, 3H); [M+H]=374.3.

Example 243.1-Benzoyl-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.38 (m, 1H), 7.46 (br s, 5H),7.39-7.19 (m, 1H), 4.87-4.46 (m, 1H), 3.99-3.35 (m, 3H), 2.87-2.55 (m,6H); [M+H]=358.3.

Example 244.1-[(3,4-Difluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.26 (m, 1H), 7.67-7.55 (m, 2H),7.39-7.33 (m, 1H), 7.31-7.16 (m, 1H), 4.94-4.58 (m, 1H), 3.98-3.73 (m,2H), 3.39-3.32 (m, 1H), 2.75-2.56 (m, 6H); [M+H]=394.2.

Example 245.3,3-Difluoro-1-[(3-fluorophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.39 (m, 1H), 7.58-7.46 (m, 1H),7.34-7.28 (m, 4H), 4.91-4.67 (m, 1H), 3.95-3.79 (m, 2H), 3.44-3.35 (m,1H), 2.80-2.59 (m, 6H); [M+H]=376.2.

Example 246.3,3-Difluoro-1-[(4-fluorophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.59 (br s, 1H), 7.67-7.42 (m, 2H), 7.31 (t,J=8.8 Hz, 3H), 5.02-4.51 (m, 1H), 3.93-3.78 (m, 2H), 3.40-3.32 (m, 1H),2.60 (s, 6H); [M+H]=376.2.

Example 247.4-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.44 (m, 1H), 8.02-7.85 (m, 2H), 7.65(br s, 2H), 7.45-7.15 (m, 1H), 4.92-4.69 (m, 1H), 4.06 (s, 3H), 2.57 (brs, 6H); [M+H]=383.3.

Example 248.1-[(3-Ethoxyphenyl)carbonyl]3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.35 (m, 1H), 7.45-7.16 (m, 2H),7.10-6.78 (m, 3H), 4.96-4.53 (m, 1H), 4.14-3.96 (m, 2H), 4.34-3.95 (m,3H), 3.94-3.61 (m, 2H), 3.52-3.31 (m, 1H), 2.60 (br s, 5H), 1.31 (t,J=6.8 Hz, 3H); [M+H]=402.3.

Example 249.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(trifluoromethoxy)phenyl]carbonyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.32 (m, 1H), 7.68-7.58 (m, 1H),7.55-7.47 (m, 2H), 7.45-7.41 (m, 1H), 7.35-7.13 (m, 1H), 4.93-4.70 (m,1H), 4.27-3.35 (m, 4H), 2.78-2.59 (m, 5H); [M+H]=442.2

Example 250.(2R)-4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.83-8.33 (m, 1H), 7.83-7.61 (m, 2H),7.54-7.46 (m, 1H), 7.46-7.40 (m, 1H), 7.35-7.21 (m, 1H), 5.65-4.99 (m,2H), 4.55-3.90 (m, 3H), 3.24-2.85 (m, 2H), 2.63 (br s, 3H); [M+H]=402.2.

Example 251.(2R)-4-[(3-Bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) d=8.70-8.44 (m, 1H), 8.02-7.85 (m, 1H),7.62-7.54 (m, 1H), 7.53-7.43 (m, 1H), 7.33-7.16 (m, 1H), 5.47-5.02 (m,2H), 4.55-3.92 (m, 3H), 3.19-2.91 (m, 2H), 2.63 (s, 3H); [M+H]=420.2.

Example 252.(2S)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.33 (m, 1H), 7.74 (t, J=1.8 Hz, 1H),7.67-7.55 (m, 2H), 7.33-7.18 (m, 1H), 5.56-5.00 (m, 2H), 4.47-3.88 (m,3H), 3.17-2.82 (m, 2H), 2.62 (br s, 3H); [M+H]=392.2.

Example 253.(2S)-4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.43 (m, 1H), 7.79-7.64 (m, 2H), 7.49(s, 1H), 7.46-7.40 (m, 1H), 7.33-7.20 (m, 1H), 5.49-4.96 (m, 2H),4.51-3.92 (m, 3H), 3.14 (s, 2H), 2.63 (br s, 3H); [M+H]=402.2.

Example 254.(2S)-4-[(3-Bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.45 (m, 1H), 8.03-7.82 (m, 1H),7.65-7.56 (m, 1H), 7.53-7.43 (m, 1H), 7.25 (br s, 1H), 5.45-5.01 (m,1H), 4.49-3.79 (m, 3H), 3.66-3.38 (m, 1H), 3.18-3.01 (m, 1H), 2.94-2.74(m, 1H), 2.63 (s, 3H); [M+H]=420.3.

Example 255.(2R)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.37 (m, 1H), 7.78-7.72 (m, 1H),7.68-7.52 (m, 2H), 7.30-7.20 (m, 1H), 5.60-5.02 (m, 2H), 4.47-3.77 (m,3H), 3.18-2.82 (m, 2H), 2.71-2.59 (m, 3H); [M+H]=392.2.

Example 256.4-[(3-Bromo-5-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.33 (m, 1H), 7.68 (s, 1H), 7.66-7.53(m, 1H), 7.47-7.42 (m, 1H), 7.33-7.20 (m, 1H), 5.54-4.99 (m, 1H),4.52-3.73 (m, 3H), 3.56-3.36 (m, 1H), 3.17-2.77 (m, 2H), 2.62 (br s,3H); [M+H]=420.2.

Example 257.4-[(3,5-Dibromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.43 (m, 1H), 7.97 (t, J=1.8 Hz, 1H),7.82-7.71 (m, 2H), 7.39-7.18 (m, 1H), 5.50-5.04 (m, 1H), 4.50-3.77 (m,3H), 3.56-3.36 (m, 1H), 3.22-2.73 (m, 2H), 2.62 (br s, 3H); [M+H]=482.1

Example 258.1-[(3-Bromo-5-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.66-8.42 (m, 1H), 7.78-7.62 (m, 1H), 7.50(t, J=1.4 Hz, 1H), 7.41-7.35 (m, 1H), 7.28-7.20 (m, 1H), 4.99-4.59 (m,1H), 4.27-3.73 (m, 3H), 2.71-2.57 (m, 6H); [M+H]=454.2.

Example 259.1-[(3,5-Dibromophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.42 (m, 1H), 8.06-7.91 (m, 1H), 7.66(d, J=1.6 Hz, 2H), 7.36-7.21 (m, 1H), 4.94-4.69 (m, 1H), 4.18-3.71 (m,3H), 2.59 (br s, 6H); [M+H]=516.1.

Example 260.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(pentafluorosulfanyl)phenyl]carbonyl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.36 (m, 1H), 8.10-7.76 (m, 4H),7.46-7.09 (m, 1H), 4.96-4.68 (m, 1H), 4.27-3.61 (m, 3H), 2.60 (br s,6H); [M+H]=484.3.

Example 261.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(pentafluorosulfanyl)phenyl]carbonyl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.77-8.27 (m, 1H), 8.10-7.63 (m, 4H),7.43-7.13 (m, 1H), 5.43-5.08 (m, 1H), 4.55-3.79 (m, 3H), 3.73-3.33 (m,2H), 3.23-2.83 (m, 1H), 2.74-2.56 (m, 3H); [M+H]=450.3.

Example 262.1-[(3-Bromo-4-methylphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.39 (m, 1H), 7.75-7.60 (m, 1H),7.52-7.36 (m, 2H), 7.32-7.19 (m, 1H), 4.91-4.51 (m, 1H), 4.33-3.34 (m,3H), 2.60 (br s, 6H), 2.37 (s, 3H); [M+H]=450.2.

Example 263.4-[(3-Bromo-4-methylphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.34 (m, 1H), 7.89-7.66 (m, 1H),7.56-7.35 (m, 2H), 7.25 (br s, 1H), 5.47-4.99 (m, 1H), 4.52-3.45 (m,4H), 3.22-2.76 (m, 1H), 2.63 (s, 3H), 2.38 (s, 3H); [M+H]=416.2.

Example 264.4-[(4-Chloropyridin-2-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.54-8.12 (m, 1H), 8.05-7.45 (m, 2H),7.21-7.05 (m, 1H), 5.56-5.21 (m, 1H), 5.14-4.73 (m, 2H), 4.37-3.70 (m,3H), 3.48-2.82 (m, 3H), 2.76-2.47 (m, 4H); [M+H]=359.0.

Example 265.4-Chloro-2-[(3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ=8.58-8.28 (m, 2H), 7.90-7.75 (m, 1H),7.47-7.32 (m, 1H), 6.94-6.80 (m, 1H), 4.97 (d, J=11.3 Hz, 1H), 4.72-4.52(m, 1H), 4.10-3.32 (m, 4H), 2.71 (d, J=13.7 Hz, 4H); [M+H]=393.0.

Example 266.2-(4-Chlorophenoxy)-3-[(3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ=8.60-8.19 (m, 2H), 7.83 (br s, 2H), 7.47-7.27(m, 2H), 7.25-6.95 (m, 3H), 4.92-3.63 (m, 7H), 2.70 (br s, 3H);[M+H]=485.2.

Example 267.4-{[2-Methyl-6-(trifluoromethyl)pyridin-3-yl]carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.54-8.12 (m, 1H), 8.05-7.41 (m, 2H),7.20-7.06 (m, 1H), 5.59-4.73 (m, 2H), 4.39-2.94 (m, 3H), 2.92-2.50 (m,6H); [M+H]=407.1.

Example 268.(5R)-1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.44 (m, 1H), 7.92-7.71 (m, 1H),7.63-7.46 (m, 2H), 7.36-7.05 (m, 1H), 5.04-3.74 (m, 4H), 2.79-2.58 (m,6H); [M+H]=456.2.

Example 269.(5S)-1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.48 (m, 1H), 7.85-7.76 (m, 1H), 7.48(s, 2H), 7.37-7.18 (m, 1H), 5.04-4.62 (m, 1H), 4.31-3.64 (m, 3H), 2.60(br s, 6H); [M+H]=456.2.

Example 270.(5R)-1-(3-Bromo-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.35 (m, 1H), 7.76-7.64 (m, 1H), 7.50(t, J=1.6 Hz, 1H), 7.42-7.35 (m, 1H), 7.30-7.17 (m, 1H), 4.93-4.67 (m,1H), 4.17-3.74 (m, 3H), 2.77-2.56 (m, 6H); [M+H]=454.2.

Example 271.(5S)-1-(3-Bromo-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.46 (br s, 1H), 7.70 (br s, 1H), 7.50 (t,J=1.4 Hz, 1H), 7.37 (qd, J=1.2, 8.6 Hz, 1H), 7.24 (br s, 1H), 4.90-4.67(m, 1H), 4.18-3.98 (m, 1H), 3.92-3.67 (m, 2H), 2.59 (br s, 6H);[M+H]=454.2.

Example 272.3-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-2-methyl-6-(trifluoromethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ=8.28-7.29 (m, 3H), 7.30-7.29 (m, 1H),6.95-6.70 (m, 1H), 4.99-4.88 (m, 1H), 5.02-4.74 (m, 1H), 3.93-3.32 (m,3H), 3.18-2.90 (m, 1H), 2.68-2.20 (m, 8H); M+H=441.0.

Example 273.(2S)-4-(3,5-Dibromobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.44 (m, 1H), 7.98 (t, J=1.8 Hz, 1H),7.79 (br s, 2H), 7.32-7.14 (m, 1H), 5.46-5.07 (m, 1H), 4.47-3.77 (m,3H), 3.55-3.38 (m, 1H), 3.16-2.76 (m, 2H), 2.64 (br s, 3H); [M+H]=482.1.

Example 274.(5R)-1-(3,5-Dibromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.38 (m, 1H), 8.09-7.92 (m, 1H), 7.68(d, J=2.0 Hz, 2H), 7.45-7.01 (m, 1H), 4.89-4.60 (m, 1H), 4.28-3.39 (m,3H), 2.61 (br s, 6H); [M+H]=516.1.

Example 275.(5S)-1-(3,5-Dibromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.44 (m, 1H), 8.09-7.92 (m, 1H), 7.68(d, J=1.6 Hz, 2H), 7.45-7.18 (m, 1H), 4.89-4.67 (m, 1H), 4.19-3.40 (m,3H), 2.62 (d, J=9.8 Hz, 6H); [M+H]=516.1.

Example 276.(5S)-1-[3,5-Bis(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.19 (m, 2H), 8.14 (s, 2H), 7.40-7.13(m, 1H), 5.04-4.69 (m, 1H), 4.15-3.35 (m, 3H), 2.57 (br s, 6H);[M+H]=494.2.

Example 277.(5S)-1-(3,5-Dimethylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.32 (m, 1H), 7.42-7.19 (m, 1H), 7.09(br s, 1H), 7.03 (d, J=0.8 Hz, 2H), 5.36-3.30 (m, 5H), 2.59 (br s, 5H),2.30 (s, 6H); [M+H]=386.3.

Example 278.(2S)-4-(3-Bromo-5-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.37 (m, 1H), 7.85 (s, 1H), 7.76-7.55(m, 2H), 7.39-7.12 (m, 1H), 5.48-4.94 (m, 1H), 4.52-3.34 (m, 4H),3.16-2.81 (m, 2H), 2.63 (d, J=10.2 Hz, 3H); [M+H]=438.1.

Example 279.(2S)-4-(3-Bromo-5-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.80-8.29 (m, 1H), 7.73-7.67 (m, 1H),7.66-7.55 (m, 1H), 7.47-7.41 (m, 1H), 7.31-7.19 (m, 1H), 5.50-5.02 (m,1H), 4.42-3.37 (m, 4H), 3.18-2.76 (m, 2H), 2.62 (br s, 3H); [M+H]=420.2.

Example 280.(5S)-1-(3,5-Dichlorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.42 (m, 1H), 7.75 (br s, 1H), 7.51 (d,J=2.0 Hz, 2H), 7.24 (br s, 1H), 5.09-3.30 (m, 5H), 2.59 (br s, 5H);[M+H]=436.3.

Example 281.(5S)-1-(4-Bromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.61-8.47 (m, 1H), 7.68 (d, J=8.2 Hz, 2H),7.44 (s, 2H), 7.33-7.20 (m, 1H), 4.92-3.32 (m, 5H), 2.79-2.54 (m, 5H);[M+H]=438.3.

Example 282.(5S)-1-(3-Bromo-2,4,5,6-tetrafluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.27 (m, 1H), 7.23 (d, J=3.9 Hz, 1H),4.93-3.35 (m, 5H), 2.76-2.56 (m, 5H); [M+H]=508.2.

Example 283.(5S)-1-(3-Cyclopropyl-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.77-8.30 (m, 1H), 7.33 (br s, 2H), 6.87 (d,J=5.5 Hz, 1H), 4.94-4.63 (m, 1H), 3.92-3.77 (m, 2H), 3.47-3.07 (m, 2H),2.81-2.53 (m, 5H), 2.18-2.03 (m, 1H), 1.11-0.94 (m, 2H), 0.89-0.69 (m,2H); [M+H]=434.4.

Example 284.(2S)-4-[3-Methyl-4-(propan-2-yloxy)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.37 (s, 1H), 7.43-7.31 (m, 2H), 7.19-7.12 (m,1H), 6.85 (d, J=8.6 Hz, 1H), 5.33-5.23 (m, 1H), 4.90 (br s, 1H), 4.58(spt, J=6.1 Hz, 1H), 4.39 (d, J=6.3 Hz, 1H), 4.21 (d, J=10.6 Hz, 1H),3.89 (t, J=11.0 Hz, 1H), 3.20 (br s, 1H), 2.90 (dd, J=10.0, 13.1 Hz,1H), 2.71 (s, 3H), 2.26 (s, 3H), 1.35 (d, J=5.9 Hz, 6H); [M+H]=395.7.

Example 285.(2S)-4-(4-Ethoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.38 (s, 1H), 7.45-7.33 (m, 2H), 7.16 (d,J=0.8 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 5.33-5.25 (m, 1H), 4.89 (br s,1H), 4.42 (br s, 1H), 4.27-4.14 (m, 1H), 4.13-4.02 (m, 2H), 3.96-3.83(m, 1H), 3.21 (br s, 1H), 2.97-2.82 (m, 1H), 2.72 (s, 3H), 2.29 (s, 3H),1.50-1.40 (m, 3H); [M+H]=381.9.

Example 286.(2S)-4-(3-Bromo-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.36 (m, 1H), 7.52 (s, 4H), 5.58-4.91(m, 1H), 4.52-3.35 (m, 4H), 3.18-2.73 (m, 2H), 2.63 (br s, 3H), 2.36 (brs, 3H); [M+H]=416.4.

Example 287.(2S)-4-(3-Chloro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.40 (m, 1H), 7.46-7.20 (m, 4H),5.58-3.78 (m, 4H), 3.64-3.47 (m, 1H), 3.16-2.81 (m, 2H), 2.63 (br s,3H), 2.37 (br s, 3H); [M+H]=372.3.

Example 288.(2S)-4-[1-Methyl-3-(propan-2-yl)-1H-pyrazole-5-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.42 (s, 1H), 7.22-7.13 (m, 1H), 6.60 (br s,1H), 5.25 (dd, J=2.2, 10.4 Hz, 1H), 5.10 (br s, 1H), 4.62 (br s, 1H),4.26 (d, J=11.0 Hz, 1H), 3.97 (s, 3H), 3.88 (t, J=11.9 Hz, 1H),3.67-3.08 (m, 1H), 3.06-2.87 (m, 2H), 2.79-2.67 (m, 4H), 1.31 (dd,J=4.9, 6.8 Hz, 7H); [M+H]=370.5.

Example 289.(2S)-4-[3,5-Dimethyl-4-(propan-2-yloxy)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.34 (br s, 1H), 7.22 (br s, 2H), 7.16 (s,1H), 5.27 (dd, J=1.6, 10.2 Hz, 1H), 4.22 (spt, J=6.1 Hz, 2H), 3.90 (t,J=10.6 Hz, 1H), 3.17 (br s, 1H), 2.90 (dd, J=10.4, 13.1 Hz, 1H), 2.72(s, 3H), 2.32 (s, 6H), 1.30 (dd, J=0.8, 5.9 Hz, 6H); [M+H]=410.7.

Examples 290-333 were prepared in a manner analogous to Example 8, withthe appropriate starting material and reagent substitutions.

Example 290.2-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.23 (m, 2H), 8.11-7.99 (m, 2H),7.91-7.62 (m, 3H), 7.41-7.20 (m, 1H), 5.06-4.81 (m, 1H), 4.42-4.31 (m,1H), 3.63-3.33 (m, 2H), 2.78-2.53 (m, 6H); [M+H]=409.3.

Example 291.4-[(3-Bromo-5-chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.73-8.36 (m, 1H), 7.85 (t, J=1.8 Hz, 1H),7.77-7.58 (m, 2H), 7.36-7.07 (m, 1H), 5.45-5.11 (m, 1H), 4.51-4.13 (m,2H), 4.06-3.75 (m, 2H), 3.13-2.74 (m, 2H), 2.62 (br s, 3H); [M+H]=438.1.

Example 292.1-[(3-Bromo-5-chlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.43 (m, 1H), 7.91-7.81 (m, 1H),7.66-7.59 (m, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.38-7.16 (m, 1H), 4.93-4.67(m, 1H), 4.15-3.73 (m, 3H), 2.59 (br s, 6H); [M+H]=472.1.

Example 293.3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline

¹H NMR (400 MHz, DMSO-d₆) δ=9.43-9.22 (m, 1H), 8.72-8.62 (m, 1H),8.27-8.19 (m, 2H), 8.10 (d, J=8.2 Hz, 1H), 7.86 (ddd, J=1.2, 7.0, 8.2Hz, 1H), 7.82-7.71 (m, 1H), 7.39-7.25 (m, 1H), 5.28 (dd, J=2.3, 10.2 Hz,1H), 4.62-4.42 (m, 1H), 4.27-3.99 (m, 1H), 3.95-3.84 (m, 1H), 3.67-3.54(m, 1H), 3.47-3.36 (m, 1H), 3.27-2.88 (m, 2H), 2.69-2.57 (m, 3H);[M+H]=375.3.

Example 294.3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=8.98 (d, J=1.6 Hz, 1H), 8.74-8.48 (m, 2H),8.07 (d, J=8.6 Hz, 2H), 7.86 (ddd, J=1.6, 6.8, 8.4 Hz, 1H), 7.80-7.63(m, 1H), 7.37-7.16 (m, 1H), 5.52-5.17 (m, 1H), 4.59-3.52 (m, 4H),3.22-2.87 (m, 2H), 2.75-2.57 (m, 3H); [M+H]=375.3.

Example 295.6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=8.97 (dd, J=2.0, 4.3 Hz, 1H), 8.47 (d, J=7.8Hz, 1H), 8.41-8.11 (m, 2H), 8.09 (d, J=8.6 Hz, 1H), 7.86 (dd, J=1.6, 8.6Hz, 1H), 7.68-7.56 (m, 1H), 7.35-7.16 (m, 1H), 5.55-5.12 (m, 1H),4.60-3.86 (m, 3H), 3.75-3.40 (m, 1H), 3.15 (d, J=5.1 Hz, 2H), 2.63 (brs, 3H); [M+H]=375.3.

Example 296.6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline

¹H NMR (400 MHz, DMSO-d₆) δ=9.38 (s, 1H), 8.59 (br s, 2H), 8.23 (d,J=8.6 Hz, 2H), 7.92 (br s, 1H), 7.77 (dd, J=1.6, 8.2 Hz, 1H), 7.41-7.15(m, 1H), 5.52-4.41 (m, 2H), 4.39-3.41 (m, 3H), 3.23-2.85 (m, 2H), 2.63(d, J=18.0 Hz, 3H); [M+H]=375.3.

Example 297.7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline

¹H NMR (400 MHz, DMSO-d₆) δ=9.40 (s, 1H), 8.58 (d, J=5.5 Hz, 1H),8.39-8.08 (m, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.95-7.83 (m, 2H), 7.43-7.18(m, 1H), 5.54-5.06 (m, 1H), 4.57-3.83 (m, 3H), 3.74-3.39 (m, 1H),3.22-2.78 (m, 2H), 2.71-2.54 (m, 3H); [M+H]=375.3.

Example 298.7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=8.98 (dd, J=1.6, 4.3 Hz, 1H), 8.43 (d, J=7.4Hz, 1H), 8.09 (d, J=8.2 Hz, 3H), 7.73-7.65 (m, 1H), 7.63-7.56 (m, 1H),7.33-7.14 (m, 1H), 5.50-5.13 (m, 1H), 4.65-3.78 (m, 3H), 3.69-3.47 (m,1H), 3.26-2.83 (m, 2H), 2.66 (d, J=11.3 Hz, 3H); [M+H]=375.3.

Example 299.1-[(4Cyclopropylphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.64-8.44 (m, 1H), 7.35 (d, J=8.2 Hz, 2H),7.31-7.25 (m, 1H), 7.18-7.12 (m, 2H), 3.94-3.76 (m, 1H), 3.68-3.51 (m,3H), 3.19-3.05 (m, 3H), 2.60 (s, 3H), 2.00-1.88 (m, 1H), 1.05-0.93 (m,2H), 0.75-0.64 (m, 2H); [M+H]=398.0.

Example 300.4-[(4Cyclopropylphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.64-8.52 (m, 1H), 7.44-7.36 (m, 2H),7.29-7.24 (m, 1H), 7.15 (d, J=8.2 Hz, 2H), 5.43-5.12 (m, 1H), 4.76-3.38(m, 4H), 3.18-2.79 (m, 2H), 2.67-2.60 (m, 3H), 2.10-1.80 (m, 1H),1.06-0.90 (m, 2H), 0.81-0.60 (m, 2H); [M+H]=364.3.

Example 301.(2S)-4-(4Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CD₃OD) δ=9.54-9.33 (m, 1H), 8.19 (d, J=7.8 Hz, 2H),8.07 (s, 1H), 8.00-7.89 (m, 2H), 6.18-5.96 (m, 1H), 5.26-4.55 (m, 3H),3.96 (s, 3H), 3.44 (s, 3H), 2.83-2.68 (m, 1H), 1.86-1.72 (m, 2H),1.60-1.46 (m, 2H); [M+H]=364.4.

Example 302.(5S)-1-(4Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.58 (s, 1H), 7.95-7.90 (m, 1H), 7.38-7.30(m, 2H), 7.30-7.24 (m, 1H), 7.20-7.09 (m, 2H), 3.95-3.32 (m, 3H),2.76-2.52 (m, 7H), 2.00-1.86 (m, 1H), 1.02-0.91 (m, 2H), 0.78-0.63 (m,2H); [M+H]=398.3.

Example 303.4-[3-Bromo-5-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.32 (m, 1H), 8.19-7.82 (m, 3H),7.32-7.13 (m, 1H), 5.47-3.40 (m, 5H), 3.19-2.94 (m, 2H), 2.68-2.56 (m,3H); [M+H]=470.2.

Example 304.1-[3-Bromo-5-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-6.93 (m, 5H), 5.01-3.44 (m, 3H),2.88-2.53 (m, 7H); [M+H]=504.2.

Example 305.(5S)-1-[3-Bromo-4-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.21-8.10 (m, 2H), 7.94 (d, J=5.5 Hz, 2H),7.69-7.60 (m, 1H), 3.85 (br s, 3H), 3.53-3.31 (m, 2H), 2.67-2.53 (m,5H); [M+H]=505.1.

Example 306.(5S)-1-(3-Bromo-5-fluoro-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.19 (m, 1H), 7.73-7.52 (m, 1H),7.39-7.09 (m, 2H), 4.94-4.69 (m, 1H), 3.91-3.34 (m, 3H), 2.76-2.53 (m,6H), 2.36-2.18 (m, 3H); [M+H]=568.2.

Example 307.(5S)-3,3-Difluoro-1-(4-fluoro-3,5-dimethylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.14 (br s, 2H), 7.38-7.14 (m, 2H), 3.89 (brs, 3H), 3.53-3.30 (m, 2H), 2.88-2.51 (m, 5H); [M+H]=404.2.

Example 308.(5S)-1-(3-Chloro-5-fluoro-4-methoxybenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.23 (m, 1H), 7.49-7.39 (m, 2H),7.36-7.19 (m, 1H), 3.94 (s, 5H), 2.67-2.57 (m, 5H); [M+H]=440.1.

Example 309.(5S)-1-(3,4-Difluoro-5-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.66-8.40 (m, 1H), 8.30-8.00 (m, 1H), 7.38(ddd, J=2.0, 7.5, 10.1 Hz, 1H), 7.24 (d, J=5.9 Hz, 2H), 3.88 (br s, 3H),3.56-3.31 (m, 2H), 2.67-2.57 (m, 5H); [M+H]=408.2.

Example 310.(5S)-1-(3,5-Dibromo-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.47 (m, 1H), 7.70 (s, 2H), 7.40-7.15(m, 1H), 5.16-3.52 (m, 3H), 3.23-2.55 (m, 7H); [M+H]=528.0.

Example 311.(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(3,4,5-trifluorobenzoyl)piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.27-8.03 (m, 1H), 7.54-7.37 (m, 2H),7.37-7.11 (m, 1H), 3.85 (d, J=3.9 Hz, 3H), 2.69-2.54 (m, 7H);[M+H]=412.1.

Example 312.(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(3,4,5-trichlorobenzoyl)piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.48 (br s, 1H), 7.74 (s, 2H), 7.23 (br s,1H), 3.37 (s, 3H), 3.28-2.72 (m, 2H), 2.67-2.51 (m, 5H); [M+H]=460.1.

Example 313.(5S)-1-(3,5-Dichloro-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.21 (m, 1H), 7.72 (d, J=6.3 Hz, 2H),7.53-7.10 (m, 1H), 4.94-4.55 (m, 1H), 4.15-3.81 (m, 2H), 3.56-3.22 (m,2H), 2.60 (br s, 5H); [M+H]=444.1.

Example 314.(5S)-1-(3-Chloro-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.75-8.32 (m, 1H), 7.75-7.47 (m, 2H),7.42-7.19 (m, 1H), 4.90-4.63 (m, 1H), 4.26-3.85 (m, 2H), 3.44-3.28 (m,1H), 2.79-2.55 (m, 6H); [M+H]=428.4.

Example 315.(5S)-1-(3-Bromo-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.72-8.40 (m, 1H), 7.65 (d, J=6.3 Hz, 2H),7.40-7.09 (m, 1H), 5.04-4.58 (m, 1H), 4.21-3.80 (m, 2H), 3.50-3.29 (m,1H), 2.60 (br s, 6H); [M+H]=472.3.

Example 316.(2S)-4-(3-Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.31 (m, 1H), 7.31 (d, J=7.8 Hz, 5H),5.43-4.92 (m, 1H), 4.40-3.69 (m, 3H), 3.48-3.32 (m, 1H), 3.14-2.72 (m,2H), 2.63 (br s, 3H), 2.07-1.93 (m, 1H), 0.98 (d, J=8.2 Hz, 2H), 0.70(td, J=2.1, 4.8 Hz, 2H); [M+H]=364.4.

Example 317.(5S)-1-(3-Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.43 (m, 1H), 7.36-7.28 (m, 2H),7.23-7.09 (m, 3H), 5.04-4.44 (m, 1H), 3.91-3.69 (m, 2H), 2.79-2.53 (m,7H), 2.02-1.92 (m, 1H), 0.97 (ddd, J=2.3, 3.9, 8.2 Hz, 2H), 0.74-0.66(m, 2H); [M+H]=398.4.

Example 318.(2S)-4-(3-Cyclopropyl-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.64 (s, 1H), 7.36-7.08 (m, 4H), 5.45-3.97(m, 3H), 3.95-2.65 (m, 4H), 2.63 (s, 3H), 2.16-1.96 (m, 1H), 1.05-0.92(m, 2H), 0.76 (br s, 2H); [M+H]=382.4.

Example 319.(5S)-1-(3-Cyclopropyl-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.57 (s, 1H), 7.40-6.85 (m, 4H), 4.82-3.83(m, 5H), 2.60 (s, 5H), 2.09-2.00 (m, 1H), 0.98 (d, J=8.6 Hz, 2H), 0.76(dd, J=5.3, 18.6 Hz, 2H); [M+H]=416.4.

Example 320.(2S)-4-(3-Cyclopropyl-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.42 (m, 1H), 7.43-7.34 (m, 1H),7.30-7.22 (m, 1H), 7.00-6.91 (m, 1H), 5.43-4.99 (m, 2H), 3.99-2.89 (m,5H), 2.64 (d, J=4.3 Hz, 3H), 2.18-2.06 (m, 1H), 1.07-1.00 (m, 2H),0.86-0.74 (m, 2H); [M+H]=400.4.

Example 321.(5S)-1-(4Cyclopropyl-3-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.83-8.34 (m, 1H), 7.35-7.03 (m, 4H),5.06-3.85 (m, 4H), 3.39-3.28 (m, 1H), 2.60 (s, 5H), 2.20-1.74 (m, 1H),1.05-0.96 (m, 2H), 0.77 (d, J=4.3 Hz, 2H); [M+H]=416.4.

Example 322.(5S)-1-(4Cyclopropyl-2,3-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.68-8.26 (m, 1H), 7.37-7.16 (m, 1H),7.14-6.72 (m, 2H), 5.06-4.45 (m, 1H), 4.04-3.75 (m, 4H), 2.77-2.54 (m,5H), 2.17-2.01 (m, 1H), 1.04 (d, J=5.9 Hz, 2H), 0.91-0.73 (m, 2H);[M+H]=434.4.

Example 323.(2S)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.83-8.27 (m, 1H), 7.43-7.15 (m, 3H), 7.07(t, J=7.8 Hz, 1H), 5.40-4.24 (m, 2H), 3.79-2.72 (m, 5H), 2.63 (s, 3H),2.12-2.01 (m, 1H), 1.05-0.98 (m, 2H), 0.86-0.67 (m, 2H); [M+H]=382.4.

Example 324.(2R)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.25 (m, 1H), 7.39-7.19 (m, 3H), 7.07(t, J=7.8 Hz, 1H), 5.35-4.43 (m, 2H), 3.85-2.81 (m, 5H), 2.63 (s, 3H),2.15-1.95 (m, 1H), 1.06-0.92 (m, 2H), 0.85-0.68 (m, 2H); [M+H]=382.4.

Example 325.(2S)-4-(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.70-8.23 (m, 1H), 7.35-7.10 (m, 2H),6.99-6.83 (m, 1H), 5.16 (br s, 1H), 4.00 (br s, 3H), 3.48-2.84 (m, 3H),2.63 (d, J=18.8 Hz, 3H), 2.19-2.00 (m, 1H), 1.09-0.99 (m, 2H), 0.81 (d,J=5.1 Hz, 2H); [M+H]=400.4.

Example 326.(2R)-4-(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.69-8.29 (m, 1H), 7.35-7.10 (m, 2H),6.97-6.83 (m, 1H), 5.26-5.10 (m, 1H), 4.50-3.93 (m, 3H), 3.50-2.77 (m,3H), 2.63 (d, J=18.8 Hz, 3H), 2.20-1.97 (m, 1H), 1.10-0.98 (m, 2H), 0.81(d, J=5.1 Hz, 2H); [M+H]=400.4.

Example 327.(5S)-1-(4-Bromo-3-chlorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.81-8.36 (m, 1H), 7.73 (s, 2H), 7.51-7.09(m, 2H), 4.89-4.71 (m, 1H), 4.35-4.10 (m, 2H), 3.57-3.29 (m, 1H), 2.61(br s, 5H); [M+H]=472.3.

Example 328.(2R)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.45 (m, 1H), 7.89 (d, J=8.2 Hz, 2H),7.47-7.36 (m, 1H), 7.34-7.15 (m, 1H), 5.46-4.89 (m, 1H), 4.42-3.99 (m,4H), 3.57-3.28 (m, 1H), 3.12-2.79 (m, 1H), 2.65 (br s, 3H); [M+H]=436.3.

Example 329.(2S)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.79-8.40 (m, 1H), 7.90 (d, J=8.2 Hz, 2H),7.50-7.36 (m, 1H), 7.25 (br s, 1H), 5.54-5.00 (m, 1H), 4.52-3.65 (m,4H), 3.13-2.72 (m, 2H), 2.65 (br s, 3H); [M+H]=436.3.

Example 330.(2S)-4-(3-Chloro-4-cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.63-7.52 (m, 1H), 7.37-6.96 (m, 4H),5.39-4.95 (m, 2H), 4.45-2.85 (m, 5H), 2.63 (s, 3H), 2.26-2.10 (m, 1H),1.12-0.98 (m, 2H), 0.80-0.69 (m, 2H); [M+H]=398.4.

Example 331.(5S)-1-(3-Chloro-4-cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71-8.40 (m, 1H), 7.50 (d, J=1.6 Hz, 1H),7.31 (d, J=1.6 Hz, 1H), 7.23-6.93 (m, 2H), 4.90-4.58 (m, 1H), 3.99-2.66(m, 6H), 2.60 (s, 3H), 2.24-2.09 (m, 1H), 1.14-0.94 (m, 2H), 0.75 (d,J=3.1 Hz, 2H); [M+H]=432.4.

Example 332.(2S)-4-(3-Fluoro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.74-8.34 (m, 1H), 7.35-7.21 (m, 1H), 7.15(dd, J=2.3, 9.0 Hz, 3H), 5.56-4.94 (m, 1H), 4.57-3.71 (m, 3H), 3.65-2.75(m, 3H), 2.71-2.56 (m, 3H), 2.45-2.29 (m, 3H); [M+H]=356.4.

Example 333.(2S)-4-(4-Fluoro-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.58 (br s, 1H), 7.48 (br s, 1H), 7.38 (brs, 1H), 7.27-7.19 (m, 2H), 5.56-5.11 (m, 1H), 4.44-3.97 (m, 6H),2.69-2.62 (m, 3H), 2.35-2.26 (m, 3H); [M+H]=356.4.

Examples 334-338 were prepared in a manner analogous to Example 6, withthe appropriate starting material and reagent substitutions.

Example 334.(3R)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.25 (m, 1H), 7.24-7.05 (m, 2H),6.97-6.78 (m, 3H), 4.85 (d, J=12.9 Hz, 1H), 4.70-3.99 (m, 3H), 3.73-3.00(m, 5H), 2.91-2.60 (m, 4H), 2.46-2.26 (m, 1H), 2.09-1.89 (m, 2H), 1.80(br s, 1H); [M+H]=377.7.

Example 335.(3S)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.36 (m, 1H), 7.17-6.79 (m, 5H),4.93-4.74 (m, 1H), 4.71-4.55 (m, 1H), 4.43-4.00 (m, 2H), 3.68-3.54 (m,1H), 3.42-3.08 (m, 4H), 2.88-2.68 (m, 4H), 2.46-2.25 (m, 1H), 2.10-1.90(m, 2H), 1.87-1.75 (m, 1H); [M+H]=377.7.

Example 336.(3S)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.49-8.25 (m, 1H), 7.23-7.04 (m, 2H),6.96-6.78 (m, 3H), 4.93-4.77 (m, 0.5H), 4.64 (d, J=12.9 Hz, 1H),4.48-4.29 (m, 1H), 4.13 (dt, J=3.5, 10.6 Hz, 1H), 4.05 (d, J=13.3 Hz,0.5H), 3.73-2.99 (m, 5H), 2.91-2.59 (m, 4H), 2.43-2.27 (m, 1H),2.09-1.89 (m, 2H), 1.80 (br s, 1H); [M+H]=377.7.

Example 337.(2R)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.76-8.37 (m, 1H), 8.19-8.01 (m, 1H), 7.93(d, J=8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.39-7.13 (m, 1H), 5.55-4.32(m, 2H), 4.26-4.12 (m, 1H), 4.04-3.35 (m, 2H), 3.19-2.79 (m, 2H), 2.63(d, J=16.4 Hz, 3H); [M+H]=472.3.

Example 338.(3R)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-2-yl)carbonyl]piperidine

¹H NMR (400 MHz, CD₃OD) δ=8.40-8.60 (m, 1H), 7.80-8.10 (m, 4H),7.40-7.60 (m, 3H), 7.05-7.25 (m, 1H), 4.60-5.00 (m, 1H), 4.20-4.35 (m,1H), 3.70-3.90 (m, 1H), 3.30-3.50 (m, 1H), 3.10-3.25 (m, 1H), 2.55-2.70(m, 3H), 2.25-2.40 (m, 1H), 1.70-2.20 (m, 3H); [M+H]=372.1.

Examples 339-347 were prepared in a manner analogous to Example 9, withthe appropriate starting material and reagent substitutions.

Example 339.1-[(4-Chloro-3-iodophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.65 (m, 1H), 7.95-8.06 (m, 1H),7.49-7.63 (m, 1H), 7.42 (dd, J=7.83, 1.96 Hz, 1H), 6.92 (br s, 1H), 3.92(br s, 2H), 3.72 (br s, 3H), 2.61-2.85 (m, 5H); [M+H]=518.1.

Example 340. 3,3-Difluoro-1-[(4-fluoro-3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.56 (s, 1H), 7.93 (d, J=4.30 Hz, 1H),7.34-7.60 (m, 1H), 7.12-7.26 (m, 1H), 6.92 (br s, 1H), 3.93 (br s, 1H),3.38 (br s, 5H), 2.64-2.76 (m, 4H); [M+H]=502.1.

Example 341.(5S)-1-(1-Benzofuran-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.40 (br s, 1H), 7.80 (s, 1H), 7.74-7.69 (m,1H), 7.57 (d, J=8.2 Hz, 1H), 7.44 (dd, J=1.6, 8.6 Hz, 1H), 6.90-6.82 (m,2H), 4.75 (br s, 1H), 3.95 (br s, 1H), 3.49 (s, 2H), 2.71 (s, 6H);[M+H]=398.5.

Example 342.(5S)-3,3-Difluoro-1-(4-methoxy-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.43 (s, 1H), 7.36-7.30 (m, 2H), 6.91-6.81 (m,2H), 4.88-4.29 (m, 2H), 3.95 (d, J=5.1 Hz, 1H), 3.87 (s, 3H), 3.63-3.32(m, 2H), 2.76-2.56 (m, 5H), 2.57-2.55 (m, 1H), 2.25 (s, 3H);[M+H]=402.58.

Example 343.(2S)-4-(4-Methoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.38 (s, 1H), 7.40 (d, J=6.3 Hz, 2H), 7.16 (s,1H), 6.88-6.83 (m, 1H), 5.32-5.26 (m, 1H), 4.21 (d, J=11.0 Hz, 2H),3.95-3.88 (m, 1H), 3.87 (s, 4H), 3.22 (br s, 1H), 2.91 (dd, J=10.2, 12.9Hz, 1H), 2.72 (s, 3H), 2.29 (s, 3H); [M+H]=368.5.

Example 344.1-(6-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.60-8.29 (m, 1H), 7.04-6.63 (m, 4H),4.98-3.95 (m, 4H), 3.71-3.53 (m, 1H), 3.47-2.97 (m, 4H), 2.71 (d, J=4.7Hz, 3H), 2.86-2.62 (m, 1H), 2.45-2.27 (m, 1H), 2.09-1.92 (m, 2H), 1.77(d, J=10.2 Hz, 1H); [M+H]=396.3.

Example 345.4-[1-(4-Fluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.60-8.13 (m, 1H), 7.49-7.35 (m, 2H),7.24-7.13 (m, 3H), 6.80-6.69 (m, 1H), 6.06-4.55 (m, 3H), 4.34-3.84 (m,2H), 3.49 (s, 1H), 3.16 (d, J=12.5 Hz, 1H), 2.73 (s, 3H), 2.41-2.28 (m,3H); [M+H]=422.1.

Example 346.1-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.53-8.18 (m, 1H), 7.43-7.15 (m, 4H), 6.86 (s,1H), 6.69-6.49 (m, 1H), 5.15-4.40 (m, 2H), 3.84-2.90 (m, 4H), 2.67 (d,J=16.4 Hz, 3H), 2.32 (d, J=16.4 Hz, 4H), 2.14-1.90 (m, 3H), 1.28 (br s,6H); [M+H]=444.5.

Example 347.4-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.13 (m, 1H), 7.39-7.27 (m, 4H), 7.18 (brs, 1H), 6.70 (s, 1H), 6.10-5.13 (m, 2H), 4.77-3.42 (m, 3H), 3.24-3.08(m, 1H), 2.96 (td, J=6.7, 13.6 Hz, 1H), 2.71 (s, 3H), 2.38-2.31 (m, 3H),1.27 (d, J=6.7 Hz, 6H); [M+H]=446.3.

Examples 348-384 were prepared in a manner analogous to Example 5, withthe appropriate starting material and reagent substitutions.

Example 348.1-[(6-Fluoronaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.26-8.72 (m, 1H), 8.05-8.18 (m, 2H), 7.96(br s, 1H), 7.76 (br s, 1H), 7.45-7.64 (m, 2H), 7.10-7.39 (m, 1H),4.42-4.93 (m, 1H), 3.99-4.24 (m, 1H), 3.69 (br s, 2H), 3.17 (s, 1H),2.88-3.11 (m, 1H), 2.61 (br s, 3H), 2.23 (d, J=10.42 Hz, 1H), 1.98 (brs, 1H), 1.73 (br s, 1H); [M+H]=390.2.

Example 349.6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidin-1-yl)carbonyl]quinoline

¹H NMR (400 MHz, DMSO-d₆) δ=9.04 (d, J=3.14 Hz, 1H), 8.59 (d, J=7.78 Hz,1H), 8.18 (br s, 2H), 8.03-8.14 (m, 1H), 7.77-7.91 (m, 1H), 7.71 (dd,J=8.22, 4.33 Hz, 1H), 7.13-7.37 (m, 1H), 4.77-4.89 (m, 1H), 4.48-4.57(m, 1H), 4.07 (br s, 1H), 3.57-3.77 (m, 2H), 2.93-3.18 (m, 1H),2.54-2.70 (m, 3H), 2.23 (d, J=12.30 Hz, 1H), 2.00 (br s, 1H), 1.74 (brs, 1H); [M+H]=373.2.

Example 350.1-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.37-8.66 (m, 1H), 7.43-7.60 (m, 2H),7.15-7.36 (m, 2H), 4.71 (br s, 1H), 3.57-4.08 (m, 2H), 3.24 (br s, 2H),2.86-3.06 (m, 1H), 2.61 (br s, 3H), 2.20 (d, J=10.04 Hz, 1H), 1.97 (d,J=11.04 Hz, 1H), 1.70 (br s, 1H); [M+H]=402.1.

Example 351.1-[(2,3-Dihydro-1-benzofuran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.43-8.63 (m, 1H), 7.06-7.37 (m, 3H),6.71-7.03 (m, 2H), 4.32-4.70 (m, 3H), 3.56-3.85 (m, 1H), 3.34-3.51 (m,1H), 3.14-3.26 (m, 2H), 2.93-3.05 (m, 1H), 2.54-2.66 (m, 3H), 2.18 (d,J=10.29 Hz, 1H), 1.88-1.96 (m, 1H), 1.53-1.78 (m, 2H); [M+H]=364.2.

Example 352.1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.48-8.61 (m, 1H), 7.04-7.26 (m, 3H),6.71-6.91 (m, 2H), 4.26-4.65 (m, 2H), 3.86-4.12 (m, 2H), 3.24-3.62 (m,3H), 2.68-3.18 (m, 3H), 2.62 (s, 3H), 2.20 (d, J=11.80 Hz, 1H),1.78-2.01 (m, 2H), 1.45-1.76 (m, 1H); [M+H]=378.2.

Example 353.1-[(3,4-Dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.52-8.66 (m, 1H), 7.24 (dd, J=16.00, 10.60Hz, 1H), 6.98-7.13 (m, 2H), 6.66-6.88 (m, 2H), 5.02-5.16 (m, 1H),3.96-4.71 (m, 2H), 3.04-3.79 (m, 3H), 2.68-2.87 (m, 2H), 2.54-2.64 (m,3H), 2.19 (br s, 1H), 1.79-2.04 (m, 4H), 1.55 (br s, 1H); [M+H]=378.2.

Example 354.1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.49-8.62 (m, 1H), 7.17-7.31 (m, 1H),6.77-7.01 (m, 4H), 5.18-5.35 (m, 1H), 4.06-4.60 (m, 4H), 3.45 (d,J=11.80 Hz, 1H), 3.17 (s, 1H), 2.67-3.01 (m, 1H), 2.56-2.65 (m, 3H),2.20 (d, J=12.30 Hz, 1H), 1.83-2.04 (m, 2H), 1.44-1.80 (m, 1H);[M+H]=380.2.

Example 355.1-[(6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.49-8.62 (m, 1H), 7.13-7.31 (m, 1H),6.65-7.01 (m, 3H), 4.98-5.16 (m, 1H), 4.29-4.66 (m, 2H), 4.03 (d,J=10.79 Hz, 1H), 3.09-3.67 (m, 2H), 2.67-2.91 (m, 3H), 2.55-2.64 (m,3H), 2.19 (d, J=8.16 Hz, 1H), 1.79-2.08 (m, 4H); [M+H]=396.2.

Example 356.2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline

¹H NMR (400 MHz, DMSO-d₆) δ=8.30-8.70 (m, 1H), 7.14-7.40 (m, 5H),4.81-5.06 (m, 1H), 4.45-4.71 (m, 2H), 4.26-4.44 (m, 1H), 3.91-4.06 (m,1H), 3.52-3.82 (m, 2H), 3.08-3.46 (m, 3H), 2.80-3.02 (m, 4H), 2.63 (s,3H), 2.58-2.58 (m, 1H), 2.16-2.37 (m, 1H), 1.93 (br s, 2H); [M+H]=391.2.

Example 357.1-[(3-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.44-8.69 (m, 1H), 7.78 (br s, 2H), 7.45 (brs, 1H), 7.27 (br s, 2H), 4.32-4.86 (m, 1H), 3.64 (t, J=10.67 Hz, 2H),3.19 (br s, 1H), 2.81-3.06 (m, 1H), 2.62 (br s, 3H), 2.19 (d, J=11.29Hz, 1H), 1.95 (br s, 1H), 1.71 (br s, 2H); [M+H]=448.1.

Example 358.1-[(4-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.37-8.61 (m, 1H), 7.75 (br s, 2H), 7.17 (brs, 3H), 4.22-4.78 (m, 1H), 3.43-4.07 (m, 2H), 2.69-3.40 (m, 2H), 2.54(br s, 3H), 2.13 (d, J=10.29 Hz, 1H), 1.75-1.96 (m, 2H), 1.48-1.73 (m,1H); [M+H]=448.1.

Example 359.4-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.26 (m, 1H), 7.25-6.80 (m, 5H),5.43-5.07 (m, 2H), 4.90-4.75 (m, 1H), 4.67 (d, J=11.7 Hz, 1H), 4.37 (d,J=11.7 Hz, 1H), 4.29-4.05 (m, 2H), 3.92-3.75 (m, 1H), 3.62-3.41 (m, 1H),3.35-2.91 (m, 4H), 2.74 (s, 3H); [M+H]=380.1.

Example 360.4-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.38 (s, 1H), 7.44 (s, 1H), 7.36 (d, J=8.6 Hz,1H), 7.16 (d, J=0.8 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 5.29 (s, 1H),5.01-4.73 (m, 1H), 4.63 (t, J=8.8 Hz, 2H), 4.39 (br s, 1H), 4.21 (d,J=11.0 Hz, 1H), 3.93-3.84 (m, 1H), 3.26 (t, J=8.8 Hz, 3H), 2.93 (dd,J=10.0, 13.1 Hz, 1H), 2.72 (s, 3H); [M+H]=366.1.

Example 361.4-[(3,5-Difluoropyridin-2-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.48-8.24 (m, 2H), 7.35 (dtd, J=2.3, 8.4, 14.8Hz, 1H), 6.98-6.77 (m, 1H), 5.11-3.75 (m, 4H), 3.69-3.31 (m, 2H),2.96-2.54 (m, 4H); [M+H]=361.1.

Example 362.1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.53-8.21 (m, 1H), 7.24-6.74 (m, 4H),5.23-2.75 (m, 11H), 2.72 (br s, 3H); [M+H]=400.1.

Example 363.1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.49-8.25 (m, 1H), 7.23-6.74 (m, 5H),5.26-4.60 (m, 2H), 4.54-3.55 (m, 3H), 3.54-3.09 (m, 3H), 2.72 (br s,6H); [M+H]=414.1.

Example 364.4-(3,4-Dichlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.76-8.33 (m, 1H), 7.90-7.79 (m, 1H), 7.74(d, J=8.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.31-7.17 (m, 1H), 5.54-5.14 (m,1H), 4.54-3.59 (m, 4H), 3.60-3.35 (m, 1H), 3.19-3.04 (m, 1H), 2.63 (brs, 3H); [M+H]=392.2.

Example 365.3,3-Difluoro-1-(7-methoxy-3,4-dihydro-2H-1-benzopyran-3-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-7.98 (m, 1H), 7.14-6.74 (m, 2H),6.58-6.30 (m, 2H), 5.21-3.81 (m, 4H), 3.75 (d, J=2.0 Hz, 3H), 3.72-2.75(m, 6H), 2.70 (s, 4H), 2.14-1.85 (m, 1H); [M+H]=444.1.

Example 366.1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.50-8.22 (m, 1H), 7.24-6.75 (m, 5H),4.93-4.55 (m, 2H), 4.44-4.02 (m, 2H), 3.68-3.02 (m, 5H), 2.92-2.61 (m,4H), 2.47-2.19 (m, 1H), 2.08-1.90 (m, 2H), 1.88-1.68 (m, 1H);[M+H]=378.6.

Example 367.1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.54-8.29 (m, 1H), 7.24-6.79 (m, 5H),4.93-4.56 (m, 2H), 4.47-3.99 (m, 2H), 3.62 (d, J=9.4 Hz, 1H), 3.52-3.01(m, 4H), 2.90-2.60 (m, 4H), 2.47-2.29 (m, 1H), 2.09-1.90 (m, 2H),1.86-1.69 (m, 1H); [M+H]=378.5.

Example 368.(2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.72-8.40 (m, 1H), 8.18-8.00 (m, 1H), 7.94(d, J=8.2 Hz, 1H), 7.75-7.62 (m, 1H), 7.35-7.16 (m, 1H), 5.62-4.37 (m,2H), 4.25-3.85 (m, 2H), 3.56-3.35 (m, 1H), 3.12 (br s, 1H), 2.88 (br s,1H), 2.63 (d, J=16.8 Hz, 3H); [M+H]=472.2.

Example 369.(2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.78-8.40 (m, 1H), 7.88-7.59 (m, 2H), 7.27(d, J=18.8 Hz, 1H), 5.58-4.99 (m, 1H), 4.07-3.82 (m, 3H), 3.64-3.41 (m,1H), 3.25-2.77 (m, 2H), 2.65 (br s, 3H); [M+H]=438.3.

Example 370.(2S)-2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-(3,4,5-trichlorobenzoyl)morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.81-8.41 (m, 1H), 7.86 (d, J=18.0 Hz, 2H),7.39-7.16 (m, 1H), 5.53-5.06 (m, 1H), 4.48-3.96 (m, 3H), 3.60-3.42 (m,1H), 3.10 (br s, 1H), 2.95-2.77 (m, 1H), 2.65 (d, J=11.7 Hz, 3H);[M+H]=426.3.

Example 371.(2S)-4-(3,5-Dichloro-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, DMSO-d₆) δ=8.52 (br s, 1H), 7.84 (br s, 2H), 7.64-7.06(m, 1H), 5.53-5.14 (m, 1H), 4.44-4.17 (m, 2H), 4.05-3.85 (m, 1H),3.61-3.33 (m, 1H), 3.16-3.01 (m, 1H), 2.91-2.78 (m, 1H), 2.64 (br s,3H); [M+H]=410.3.

Example 372.(2S)-4-(1-Benzofuran-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, CD₃OD) δ=8.29 (br s, 1H), 7.82 (br s, 1H),7.73-7.64 (m, 1H), 7.58-7.51 (m, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.16 (s,1H), 6.84 (d, J=1.6 Hz, 1H), 5.27 (dd, J=2.0, 10.2 Hz, 1H), 4.93-3.79(m, 4H), 3.24 (br s, 1H), 3.02-2.82 (m, 1H), 2.70 (s, 4H); [M+H]=364.1.

Example 373.(2S)-4-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.45 (br s, 1H), 7.38-7.26 (m, 3H), 7.13 (d,J=8.2 Hz, 1H), 5.22 (d, J=9.4 Hz, 1H), 4.81-3.70 (m, 4H), 3.21 (br s,1H), 3.03-2.86 (m, 1H), 2.73 (s, 3H); [M+H]=404.6.

Example 374.(2S)-4-(1-Methyl-3-phenyl-1H-pyrazole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, CD₃OD) δ=8.29 (br s, 1H), 7.75 (br s, 2H),7.49-7.27 (m, 4H), 7.25-6.92 (m, 1H), 5.23 (d, J=8.2 Hz, 1H), 5.14-4.04(m, 3H), 3.98 (s, 3H), 3.93-3.76 (m, 1H), 3.08 (br s, 2H), 2.78-2.60 (m,3H); [M+H]=404.2.

Example 375.(2S)-4-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.30 (m, 1H), 7.25-7.05 (m, 3H),6.99-6.81 (m, 2H), 5.41-4.62 (m, 3H), 4.50-3.75 (m, 4H), 3.60-3.45 (m,1H), 3.26-2.61 (m, 7H); [M+H]=380.1.

Example 376.(2S)-4-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-morpholine

¹H NMR (400 MHz, CDCl₃) δ=8.49-8.41 (m, 1H), 7.24-6.99 (m, 3H),6.94-6.80 (m, 2H), 5.42-4.79 (m, 2H), 4.75-3.77 (m, 5H), 3.54-2.66 (m,8H); [M+H]=380.6.

Example 377.1-[(2S)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.52-8.20 (m, 1H), 7.03-6.70 (m, 5H),5.16-3.09 (m, 7H), 2.94-2.57 (m, 4H), 2.44-2.23 (m, 1H), 2.12-1.70 (m,3H); [M+H]=380.4.

Example 378.1-(2,3-Dihydro-1-benzofuran-6-carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.41 (br s, 1H), 7.25-7.08 (m, 1H), 6.96-6.68(m, 3H), 4.93-2.83 (m, 9H), 2.69 (s, 3H), 2.42-1.89 (m, 4H);[M+H]=364.4.

Example 379.1-[(2R)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.51-8.13 (m, 1H), 7.02-6.69 (m, 5H),5.16-2.75 (m, 8H), 2.72 (s, 3H), 2.46-2.24 (m, 1H), 2.11-1.70 (m, 3H);[M+H]=380.1.

Example 380.4-[1-(2-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, D₂O) δ=8.53-8.15 (m, 1H), 8.10-7.75 (m, 2H),7.42-7.17 (m, 4H), 7.02 (d, J=2.7 Hz, 1H), 6.11-5.11 (m, 2H), 4.35-4.14(m, 1H), 4.03-3.89 (m, 1H), 3.64-2.79 (m, 3H), 2.74 (s, 3H);[M+H]=408.1.

Example 381.4-[1-(2-Chlorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, D₂O) δ=8.58-8.14 (m, 1H), 7.93-7.80 (m, 1H),7.64-7.32 (m, 4H), 7.21 (s, 1H), 7.01 (d, J=2.0 Hz, 1H), 5.99-5.11 (m,2H), 4.74 (d, J=14.1 Hz, 1H), 4.33-4.10 (m, 1H), 4.04-3.82 (m, 1H),3.64-2.80 (m, 2H), 2.73 (br s, 3H); [M+H]=424.0.

Example 382.4-[1-(3-Bromophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, D₂O) δ=8.55-8.23 (m, 1H), 7.99-7.83 (m, 2H),7.71-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.35 (q, J=8.1 Hz, 1H), 7.25-7.17(m, 1H), 7.09-6.96 (m, 1H), 6.06-5.11 (m, 2H), 4.71 (br s, 1H),4.35-4.15 (m, 1H), 4.03-3.89 (m, 1H), 3.67-2.81 (m, 2H), 2.74 (s, 3H);[M+H]=468.0.

Example 383.4-[1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃ and D₂O) δ=8.54-8.14 (m, 1H), 7.55-7.35 (m, 4H),7.21 (br s, 1H), 6.74 (s, 1H), 6.06-4.65 (m, 3H), 4.69 (br s, 1H),4.35-2.78 (m, 5H), 2.73 (s, 3H), 2.41-2.33 (m, 3H); [M+H]=438.1.

Example 384.4-[1-(3-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

¹H NMR (400 MHz, CDCl₃, D₂O) δ=8.57-8.32 (m, 1H), 7.95 (d, J=2.7 Hz,1H), 7.75-7.37 (m, 3H), 7.30-7.00 (m, 3H), 6.23-5.14 (m, 2H), 4.73 (d,J=14.5 Hz, 1H), 4.40-4.14 (m, 1H), 4.03-3.88 (m, 1H), 3.72-2.82 (m, 2H),2.75 (s, 3H); [M+H]=408.2.

Examples 385-564 were prepared in a manner analogous to Example 7, withthe appropriate starting material and reagent substitutions.

Example 385.4-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 386.2-Methoxy-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=353.2.

Example 387.3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=323.2.

Example 388.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,6-naphthyridine

[M+H]=374.2.

Example 389.3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline

[M+H]=373.2.

Example 390.3-Methyl-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 391.2-Methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 392.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=323.2.

Example 393.3-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 394.1-({Imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=362.2.

Example 395.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=323.2.

Example 396.7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline

[M+H]=373.2.

Example 397.7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline

[M+H]=373.2.

Example 398.3-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 399.1-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline

[M+H]=373.2.

Example 400.2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 401.3-Chloro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=357.2.

Example 402.2-Methoxy-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=353.2.

Example 403.3-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=341.1.

Example 404.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-({2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)piperidine

[M+H]=376.2.

Example 405.3-Chloro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine

[M+H]=357.1.

Example 406.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline

[M+H]=373.2.

Example 407.6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline

[M+H]=373.2.

Example 408.1-({Imidazo[1,2-a]pyridin-2-yl}-carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=362.2.

Example 409.1-[(1-Methyl-1H-pyrrol-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=325.2.

Example 410.1-[(2-Methoxy-5-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 411.1-[(1,3-Dimethyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=340.2.

Example 412.1-[(2-Fluoro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 413.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-1-yl)carbonyl]piperidine

[M+H]=372.2.

Example 414.1-[(3-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

[M+H]=356.1.

Example 415.1-[(2-Fluoro-4-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 416.1-[(2-Methoxy-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 417.1-[(3-Fluoro-5-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 418.1-[(2-Fluoro-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 419.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoxaline

[M+H]=374.2.

Example 420.1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indole

[M+H]=375.2.

Example 421.6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidin-1-yl)carbonyl]-1,3-benzothiazole

[M+H]=379.1.

Example 422.1-[(3-Methoxy-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 423.1-[(1-Benzofuran-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=362.2.

Example 424.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]piperidine

[M+H]=376.2.

Example 425.1-[(3-Cyclopropyl-1,2-oxazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=353.2.

Example 426.1-[(2-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.1.

Example 427.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenylphenyl)carbonyl]piperidine

[M+H]=398.2.

Example 428.1-[(2,3-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=358.1.

Example 429.1-[(5-Cyclopropyl-1,2-oxazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=353.2.

Example 430.1-[(1-Methyl-5-phenyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.2.

Example 431.1-[(1,5-Dimethyl-1H-pyrazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=340.2.

Example 432.1-[(1,5-Dimethyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=340.2.

Example 433.1-[(2,5-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=358.1.

Example 434.1-[(5-Cyclopropyl-1,2-oxazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=353.2.

Example 435.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine

[M+H]=354.2.

Example 436.1-[(2,4-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=390.1.

Example 437.1-{[1-Methyl-3-(propan-2-yl)-1H-pyrazol-5-yl]carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=368.2.

Example 438.1-[(2,5-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=390.1.

Example 439.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]piperidine

[M+H]=388.2.

Example 440.1-[(4-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 441.1-[(5-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 442.1-[(3,4-Dimethoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=382.2.

Example 443.1-[(1-Ethyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=340.2.

Example 444.1-[(4-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=356.1.

Example 445.1-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.2.

Example 446.1-[(1-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.2.

Example 447.1-[(6-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.2.

Example 448.1-[(2H-1,3-Benzodioxol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.1.

Example 449.1-[(3-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.2.

Example 450.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(propan-2-yl)phenyl]carbonyl}piperidine

[M+H]=364.2.

Example 451.1-[(2,3-Dimethoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=382.2.

Example 452.1-[(1-Benzothiophen-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=378.1.

Example 453.1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=380.2.

Example 454.1-[(2,4-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=350.2.

Example 455.1-[(2-Methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=352.2.

Example 456.1-[(2-Fluoro-5-methoxyphenyl)carbonyl]3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 457.1-[(1-Benzothiophen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=378.1.

Example 458.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yl)phenyl]carbonyl}piperidine

[M+H]=364.2.

Example 459.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,3-benzothiazole

[M+H]=379.1.

Example 460.1-[(5-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 461.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3-phenylphenyl)carbonyl]piperidine

[M+H]=398.2.

Example 462.1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indazole

[M+H]=376.2.

Example 463.1-[(1-Benzofuran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=362.2.

Example 464.1-[(3-Methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=352.2.

Example 465.1-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indole

[M+H]=375.2.

Example 466.1-[(2,5-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=350.2.

Example 467.1-[(4-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 468.1-[(3-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.2.

Example 469.1-[(3-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 470.1-[(1-Benzothiophen-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=378.1.

Example 471.1-[(3-Chloro-5-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 472.1-[(2,6-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=358.1.

Example 473.1-[(Dimethyl-1,3-thiazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=357.1.

Example 474.1-[(5-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 475.1-[(4-Fluoro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 476.2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile

[M+H]=347.2.

Example 477.2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-2H-indazole

[M+H]=376.2.

Example 478.2-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidin-1-yl)carbonyl]pyridine

[M+H]=337.2.

Example 479.1-Benzoyl-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=322.2.

Example 480.1-[(4-Chloro-3-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 481.1-[(4-Methoxy-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 482.1-[(2-Chloro-5-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 483.1-[(3-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=374.1.

Example 484.1-[(4-Fluoro-2-methylphenyl)carbonyl]3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 485.1-[(2,4-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

[M+H]=358.1.

Example 486.1-[(3,4-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=358.1.

Example 487.1-[(2,3-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=350.2.

Example 488.1-[(2-Chloro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=370.1

Example 489.1-{[4-(Difluoromethyl)phenyl]carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=372.2.

Example 490.4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile

[M+H]=347.2.

Example 491.1-[(4-Methoxy-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=366.2.

Example 492.1-[(2-Fluoro-5-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=354.2.

Example 493.3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(4-phenylphenyl)carbonyl]piperidine

[M+H]=398.2.

Example 494.1-[(2,6-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.27-8.61 (m, 1H), 7.03-7.24 (m, 3H),6.75-6.97 (m, 1H), 4.80-5.04 (m, 1H), 3.53-4.01 (m, 2H), 2.87-3.52 (m,2H), 2.66-2.78 (m, 5H), 2.27-2.49 (m, 4H), 2.03-2.25 (m, 3H), 1.60-2.02(m, 2H); [M+H]=350.1.

Example 495.1-[(2-Chloro-6-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.23-8.65 (m, 1H), 7.28-7.41 (m, 2H), 7.15 (d,J=11.04 Hz, 1H), 6.80-7.12 (m, 1H), 4.40-4.89 (m, 1H), 3.95-4.21 (m,1H), 3.59-3.87 (m, 1H), 2.91-3.52 (m, 2H), 2.71-2.76 (m, 4H), 2.31 (brs, 2H), 1.67-1.95 (m, 1H); [M+H]=374.0.

Example 496.1-[(2-Fluoro-6-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.22-8.65 (m, 1H), 7.28-7.41 (m, 1H),6.85-7.20 (m, 1H), 6.58-6.84 (m, 2H), 4.30-4.75 (m, 1H) 3.98-4.27 (m,1H), 3.60-3.96 (m, 4H), 3.13-3.54 (m, 2H), 2.72-2.76 (m, 4H), 1.81-2.38(m, 3H), 1.81-2.38 (m, 3H), 1.56-1.78 (m, 1H); [M+H]=370.1.

Example 497.1-[(2-Chloro-6-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

¹H NMR (400 MHz, CDCl₃) δ=8.29-8.67 (m, 1H), 7.27-7.37 (m, 1H),7.10-7.26 (m, 2H), 6.81-7.10 (m, 1H), 4.43-5.02 (m, 1H) 3.67-4.20 (m,2H), 3.31-3.64 (m, 1H), 2.91-3.28 (m, 1H), 2.67-2.79 (m, 3H), 2.50 (s,1H), 2.27-2.42 (m, 3H), 2.17 (s, 1H), 1.81-2.10 (m, 1H), 1.57-1.80 (m,1H); [M+H]=370.1.

Example 498.2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1-methyl-1H-indole

[M+H]=411.5.

Example 499.1-(1-Benzofuran-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=398.4.

Example 500.3,3-Difluoro-1-(4-methoxy-2-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.5.

Example 501.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(5,6,7,8-tetrahydronaphthalene-2-carbonyl)piperidine

[M+H]=412.5.

Example 502.3-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1-methyl-1H-indole

[M+H]=411.4.

Example 503.1-(1-Benzothiophene-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=414.4.

Example 504.1-(3-Chloro-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=410.4.

Example 505.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(4-phenylbenzoyl)piperidine

[M+H]=434.5.

Example 506.3,3-Difluoro-1-(2-methoxy-4-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.5.

Example 507.3,3-Difluoro-1-{imidazo[1,2-a]pyridine-6-carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=398.4.

Example 508.2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)quinoxaline

[M+H]=410.4.

Example 509.3,3-Difluoro-1-{imidazo[1,2-a]pyridine-2-carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=398.4.

Example 510.1-(1-Benzothiophene-3-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=414.4.

Example 511.3,3-Difluoro-1-(2-methoxy-5-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.4.

Example 512.1-[4-(Difluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=408.4.

Example 513.1-(3,4-Dimethoxybenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=418.5.

Example 514.1-(5-Chloro-2-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=410.4.

Example 515.3,3-Difluoro-1-(4-fluoro-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=390.4.

Example 516.3,3-Difluoro-1-(4-methoxy-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.5.

Example 517.3,3-Difluoro-1-(3-methoxybenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=388.4.

Example 518.1-(2H-1,3-Benzodioxole-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=402.4.

Example 519.1-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=416.4.

Example 520.3,3-Difluoro-1-(3-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-piperidine

[M+H]=438.5.

Example 521.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[4-(propan-2-yl)benzoyl]piperidine

[M+H]=400.5.

Example 522.3,3-Difluoro-1-(2-fluoro-5-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=390.4.

Example 523.3,3-Difluoro-1-(3-fluoro-5-methoxybenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=406.4.

Example 524.1-(2,3-Dihydro-1H-indene-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=398.5.

Example 525.3,3-Difluoro-1-(1-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=438.5.

Example 526.3,3-Difluoro-1-(6-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=438.5.

Example 527.3,3-Difluoro-1-(1-methyl-3-phenyl-1H-pyrazole-5-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=438.5.

Example 528.3,3-Difluoro-1-(6-fluoronaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=426.5.

Example 529.2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1,3-benzothiazole

[M+H]=415.4.

Example 530.1-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=438.4.

Example 531.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[3-(propan-2-yl)benzoyl]piperidine

[M+H]=400.5.

Example 532.3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(1-phenyl-1H-pyrazole-4-carbonyl)piperidine

[M+H]=424.5.

Example 533.1-Methyl-2-(2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine-4-carbonyl)-1H-indole

[M+H]=377.4.

Example 534.4-(1-Benzofuran-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=364.4.

Example 535.4-(1-Benzothiophene-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=380.4.

Example 536.4-(3-Chloro-5-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=376.4.

Example 537.4-(2-Methoxy-4-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-morpholine

[M+H]=368.5.

Example 538.4-{Imidazo[1,2-a]pyridine-6-carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=364.4.

Example 539.4-(1-Benzofuran-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-morpholine

[M+H]=364.4.

Example 540.2-(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine-4-carbonyl)quinoxaline

[M+H]=376.4.

Example 541.4-(1-Benzothiophene-3-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=380.4.

Example 542.4-(2-Methoxy-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=368.4.

Example 543.4-[4-(Difluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=374.4.

Example 544.4-(3,4-Dimethoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=384.4.

Example 545.4-(5-Chloro-2-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=376.4.

Example 546.4-(4-Fluoro-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=356.4.

Example 547.4-(4-Methoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=368.4.

Example 548.4-(3-Methoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=354.4.

Example 549.4-(2H-1,3-Benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=368.4.

Example 550.4-(2-Methoxypyridine-4-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=355.4.

Example 551.4-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=382.4.

Example 552.4-(3-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=404.5.

Example 553.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[4-(propan-2-yl)benzoyl]morpholine

[M+H]=366.5.

Example 554.4-(2-Fluoro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=356.4.

Example 555.4-(3-Fluoro-5-methoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=372.4.

Example 556.4-(1-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=404.5.

Example 557.4-(6-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=404.5.

Example 558.4-(1-Methyl-3-phenyl-1H-pyrazole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=404.5.

Example 559.4-(6-Fluoronaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=392.4.

Example 560.4-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=404.4.

Example 561.2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[3-(propan-2-yl)benzoyl]morpholine

[M+H]=366.5.

Example 562.3,3-Difluoro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=432.5.

Example 563.1-(3,4-Dihydro-2H-1-benzopyran-2-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine

[M+H]=414.5.

Example 564.4-(3,4-Dihydro-2H-1-benzopyran-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine

[M+H]=380.4.

Example 565.(3,5-Dibromophenyl)(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)methanone-d₄

A solution of(3,5-dibromophenyl)(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)methanone(30.00 mg, 0.00 mol) in CD₃OD (0.35 mL, 0.18 mol/L) was treated withDIEA (5.44 μL) at 65° C. for 4 days. The solution was cooled to roomtemperature. The solid was filtered and washed with heptane. ¹H NMR (400MHz, DMSO-d₆) ppm 2.61-2.68 (m, 1H) 3.06-3.16 (m, 1H) 3.40-3.55 (m, 1H)3.86-4.02 (m, 1H) 4.13-4.47 (m, 2H) 7.16-7.36 (m, 1H) 7.72-7.87 (m, 2H)7.97-8.03 (m, 1H) 8.48-8.72 (m, 1H); [M+H]=486.1.

Example 566 was made in a manner analogous to Example 565.

Example 566.(3-Bromo-4-fluorophenyl)(3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methanone-d₄

¹H NMR (400 MHz, CD₃OD) ppm 2.64-2.76 (m, 2H) 3.34-3.60 (m, 2H) 4.56 (s,2H) 7.14-7.30 (m, 1H) 7.34-7.46 (m, 1H) 7.52-7.62 (m, 1H) 7.79-7.91 (m,1H) 8.43-8.63 (m, 1H); [M+H]=459.1.

Pharmacological Examples

The present disclosure will be further illustrated by the followingpharmacological examples. These examples are understood to be exemplaryonly and are not intended to limit the scope of the invention disclosedherein.

Enzymatic Assay

An IMAP TR-FRET-based phosphodiesterase assay was developed using thePDE2A isoform. IMAP technology is based on high-affinity binding ofphosphate by immobilized metal (MIII) coordination complexes onnanoparticles. The IMAP “binding reagent” recognizes phosphate groups onAMP or GMP generated from cAMP or cGMP in a PDE reaction. Cyclicnucleotides that carry a phosphodiester bond and not a free phosphateare not recognized by the binding reagent. The time resolvedfluorescence resonance energy transfer (TR-FRET) is afforded by aTerbium (Tb)-Donor pre-bound to the nanoparticles. FRET occurs when thefluorescent-labeled AMP or GMP product of a PDE reaction binds and comesinto close proximity to the Tb-Donor complex. Due to the long lifetimeof Tb fluorescence, detection can be run in time-resolved mode to reduceor eliminate interference from auto-fluorescent compounds.

The IMAP TR-FRET PDE2A assay was performed in 1536-well white plates. Atotal of 250 pg per well of FLAG-tagged PDE2A1 (amino acids 2-941) wasdispensed in 2.5 μL IMAP assay buffer consisting of 10 mM Tris pH 7.2,10 mM MgCl₂, 1 mM DTT, and 0.1% fatty acid free BSA. 30 nL of compoundwas then added from 1 mM stocks in DMSO using a Kalypsys Pintool. Plateswere incubated for 5 min at room temperature before dispensing 1.5 μL of533 nM FAM-cAMP substrate for a final concentration of 200 nM. Followinga brief centrifugation, plates were incubated for 30 min at roomtemperature. The assay was terminated by adding 5 μL IMAP bindingreagent Tb complex to each well which was prepared according tomanufacturer's recommendations (Molecular Devices). Plates wereincubated an additional 90 minutes at room temperature and read on aViewlux plate reader. All compounds were solvated at a concentration of10 mM in DMSO and tested in 11-point half-log dose-response. Curvefitting and IC₅₀ values were determined using a standard four parameterfit.

PDE2 (pIC₅₀) Example Numbers >7 1, 4, 5, 6, 9, 83, 109, 120, 134, 139,141, 150, 174, 178, 179, 182, 184, 186, 190, 195, 196, 197, 200, 207,208, 209, 210, 211, 225, 232, 233, 234, 235, 239, 242, 253, 254, 257,258, 259, 262, 263, 268, 269, 270, 271, 273, 274, 275, 276, 277, 278,279, 280, 281, 282, 283, 285, 286, 287, 289, 290, 291, 292, 293, 294,295, 296, 299, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 312,313, 314, 315, 316, 317, 319, 321, 322, 327, 329, 330, 331, 335, 336,338, 339, 340, 341, 342, 343, 344, 346, 348, 349, 350, 352, 353, 355,357, 358, 362, 363, 365, 366, 367, 368, 370, 372, 374, 375, 377, 378,382, 384, 389, 394, 396, 397, 406, 407, 414, 419, 420, 421, 423, 424,439, 442, 445, 446, 447, 448, 449, 452, 453, 457, 461, 463, 465, 475,481, 493, 498, 499, 501, 502, 503, 504, 505, 507, 508, 509, 510, 511,513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526,527, 528, 529, 530, 532, 534, 535, 547, 552, 557, 558, 559, 562, 563 6-72, 3, 7, 8, 12, 13, 14, 15, 16, 17, 18, 20, 21, 23, 29, 31, 34, 36, 38,41, 45, 56, 57, 60, 68, 69, 76, 77, 91, 92, 93, 95, 104, 106, 110, 125,127, 129, 132, 135, 136, 137, 140, 142, 143, 144, 145, 147, 148, 154,155, 159, 160, 161, 165, 166, 168, 169, 170, 172, 173, 180, 181, 183,185, 187, 188, 189, 191, 193, 201, 202, 205, 214, 217, 218, 219, 220,222, 226, 228, 230, 231, 236, 237, 238, 240, 241, 243, 244, 245, 246,248, 249, 252, 256, 260, 265, 266, 297, 298, 300, 311, 318, 320, 323,325, 328, 332, 333, 351, 354, 356, 359, 360, 364, 369, 371, 373, 379,380, 381, 383, 385, 386, 388, 393, 401, 402, 408, 409, 410, 411, 412,413, 415, 416, 417, 418, 425, 430, 434, 435, 436, 437, 438, 440, 444,450, 454, 455, 456, 458, 459, 462, 464, 466, 467, 470, 471, 474, 479,480, 489, 491, 492, 500, 506, 512, 531, 533, 536, 538, 539, 540, 541,542, 544, 546, 549, 551, 556, 561, 564 5-6 10, 11, 19, 22, 24, 25, 26,27, 28, 30, 32, 33, 35, 37, 39, 49, 53, 66, 79, 86, 88, 94, 98, 100,101, 102, 103, 112, 113, 114, 116, 117, 118, 124, 126, 130, 133, 138,146, 149, 151, 152, 153, 156, 157, 158, 162, 163, 164, 167, 171, 175,176, 177, 192, 194, 198, 199, 203, 204, 206, 212, 213, 215, 216, 221,227, 229, 247, 251, 261, 264, 272, 288, 324, 326, 334, 345, 347, 376,387, 392, 403, 422, 427, 428, 431, 432, 433, 443, 451, 460, 468, 469,473, 476, 478, 482, 483, 484, 485, 486, 487, 488, 490, 494, 496, 537,545, 548, 550, 553, 554, 555, 560 <5 40, 42, 43, 44, 46, 47, 48, 50, 51,52, 54, 55, 58, 59, 61, 62, 63, 64, 65, 67, 70, 71, 72, 73, 74, 75, 78,80, 81, 82, 84, 85, 87, 89, 90, 96, 97, 99, 105, 107, 108, 111, 115,119, 121, 122, 123, 128, 131, 223, 224, 250, 255, 267, 284, 337, 361,390, 391, 395, 398, 399, 400, 404, 405, 426, 429, 441, 472, 477, 495,497, 543

Biological Examples

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary onlyand are not intended to limit the scope of the invention disclosedherein.

Behavioral Assays

Numerous behavioral assays are available to assess the ability of acandidate compound to enhance memory formation, including contextualconditioning (e.g., fear conditioning), temporal conditioning (e.g.,trace conditioning), and object recognition. Other non-limiting examplesof appropriate assays to assess memory include those that incorporate orrelate to multiple training sessions, spaced training sessions,contextual fear training with single or multiple trials, trace fearconditioning with single or multiple trials, contextual memorygenerally, temporal memory, spatial memory, episodic memory, passiveavoidance memory, active avoidance memory, food preference memory,conditioned taste avoidance, and social recognition memory.

The behavioral assays can also be used in accordance with the presentinvention, as will be understood by those of ordinary skill in the art.These assays can be directed towards the evaluation of, withoutlimitation, hippocampus-, cortex, and/or amygdala-dependent memoryformation or cognitive performance.

Biological Example 1

Effect of Pde2 Inhibitors on Contextual Memory

Rationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. The percent oftime during the test that the animal exhibits such freezing provides aquantitative measure of the contextual associative memory (e.g.,Fanselow, Behav. Neurosci. 1984, 98, 269-277; Fanselow, Behav. Neurosci.1984, 98, 79-95; and Phillips and LeDoux, Behav. Neurosci. 1992, 106,274-285).

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (e.g., Phillips andLeDoux, Behav. Neurosci. 1992, 106, 274-285; Kim et al., Behav.Neurosci. 1993, 107, 1093-1098; and Bourtchouladze et al., Learn. Mem.1998, 5, 365-374). Studies in mice and rats provided evidence forfunctional interaction between hippocampal and nonhippocampal systemsduring contextual conditioning training (e.g., Maren et al., Behav.Brain Res. 1997, 88, 261-274; Maren et al., Neurobiol. Learn. Mem. 1997,67, 142-149; and Frankland et al., Behav. Neurosci. 1998, 112, 863-874).Specifically, post-training lesions of the hippocampus (but notpre-training lesions) greatly reduced contextual fear, implying that: 1)the hippocampus is essential for contextual memory but not forcontextual learning per se and 2) in the absence of the hippocampusduring training, non-hippocampal systems can support contextualconditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning, as well as strainand genetic background differences in mice (e.g., Bourtchouladze et al.,Cell 1994, 79, 59-68; Bourtchouladze et al., Learn Mem. 1998, 5,365-374; Kogan et al., Current Biology 1997, 7, 1-11; Silva et al.,Current Biology 1996, 6, 1509-1518; Abel et al., Cell 1997, 88, 615-626;Giese et al., Science 1998, 279, 870-873; Logue et al., Neuroscience1997, 80, 1075-1086; Chen et al., Behav. Neurosci. 1996, 110, 1177-1180;and Nguyen et al., Learn Mem. 2000, 7, 170-179).

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory(e.g., Kim et al., Behav. Neurosci. 1993, 107, 1093-1098; Bourtchouladzeet al., Cell 1994, 79, 59-68; Abel et al., Cell 1997, 88, 615-626; Logueet al., Behav. Neurosci. 1997, 111, 104-113; Bourtchouladze et al.,Learn. Mem. 1998, 5, 365-374; and Nguyen et al., Learn. Mem. 2000, 7,170-179). As such, contextual conditioning provides an excellent modelto evaluate the effects of novel drug compounds on hippocampal-dependentmemory formation.

Procedures

Previous investigations have established that training with 1× or2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice(e.g., U.S. 2009/0053140; Tully et al., Nat. Rev. Drug Discov. 2003, 2,267-77; and Bourtchouladze et al. Learn. Mem. 1998, 5, 365-374). Suchsub-maximal memory is facilitated by augmenting CREB, while inhibitionof CREB impairs maximal memory induced with 5×CS-US pairings (Barad etal. Proc Natl Acad Sci. 1998, 95, 15020-15025; Peters et al. Genes BrainBehav. 2009, 8, 320-329). Accordingly, contextual conditioning in thisstudy was performed as described by Barad et al. Proc Natl Acad Sci.1998, 95, 15020-15025 and Peters et al. Genes Brain Behav. 2009, 8,320-329. Young-adult (10-12 weeks old) C57BL/6 male mice or Long-Evansmale rats were used. Mice and rats were group-housed in standardlaboratory and maintained on a 12:12 light-dark cycle. The experimentswere always conducted during the light phase of the cycle. With theexception of testing times, the animals had ad libidum access to foodand water. To assess contextual memory, a modified contextual fearconditioning task originally developed for evaluation of memory in CREBknock-out mice was used (Bourtchouladze et al., 1994). Training sessionscomprised a baseline period in the conditioning chamber (Med Associates,Inc.) followed by presentation of unconditioned stimuli (1-5 footshockseach at 0.2-1.0 mA for 2-sec) spaced at 60-sec intervals. Thirty secondsfollowing the last shock, the animal was returned to its home cage. Oneto 7 days later, the animals were returned to the chamber and freezingbehavior was scored. Freezing (complete immobility except respiration)was scored by Video Freeze software (Med Associates, Inc.) over an 8minute test period. Treatment with cognition enhancers is expected tosignificantly increase freezing when compared to controls.

All experiments were designed and performed in a counterbalancedfashion. In each experiment, the experimenter was unaware (blind) to thetreatment of the subjects during training and testing. Training and testsessions were recorded as digital video files. Data were analyzed byone-way ANOVA with appropriate post-hoc tests using GraphPad Prismsoftware package.

Results

Exemplary compounds were found to enhance contextual memory in the fearconditioning assay. Significant enhancing effects were seen at severalconcentrations, including 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and3 mg/kg.

Biological Example 2

Effect of Pde2 Inhibitors on Novel Object Recognition

Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, it takes advantage of the spontaneous preference ofrodents to investigate a novel object compared with a familiar one. Itis an ethologically relevant task, which in contrast to fearconditioning, does not result from negative reinforcement (foot shock)(e.g., Ennaceur and Delacour, Behav. Brain Res. 1988, 31, 47-59).

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. In object recognition, the task relies on thenatural curiosity of rodents to explore novel objects in theirenvironments more than familiar ones. Obviously, for an object to be“familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze et. al., Proc. Natl. Acad.Sci. USA 2003, 100, 10518-10522).

Neuroimaging, pharmacological, and lesion studies have demonstrated thatthe hippocampus and adjacent perirhinal cortex are critical for objectrecognition memory in rodents, monkeys, and humans (e.g., Mitchell,Behav. Brain Res. 1998, 97, 107-113; Teng et al., J. Neurosci. 2000, 20,3853-3863; Mumby, Brain Res. 2001, 127, 159-181; Eichenbaum et al.,Annu. Rev. Neurosci. 2007, 30, 127-152; Squire et al., Nat. Rev.Neurosci. 2007, 8, 872-883; and Vann and Alabasser, Curr. Opin.Neurobiol. 2011, 21, 440-445). Hence, object recognition provides anexcellent behavioral model to evaluate drug-compound effects oncognitive tasks associated with function of the hippocampus and cortex.

Procedures

Object recognition was tested in young Long-Evans hooded male rats usingthe following protocol. Animals were briefly handled by the experimenter2-5 days prior to training. Each compound was administered between 15minutes and 24-hours prior to, or following, training. Habituationsessions (duration 1-20 min, over 1-3 days) were conducted tofamiliarize the animal to the arena. During training trials (duration of1-20 min) the animals were allowed to explore two identical objects. Atest trial (duration of 1-20 min) was then performed 1-96 hrs later.

For novel object recognition, one object was replaced with one that isnovel. All combinations and locations of objects were used in a balancedmanner to reduce potential biases attributable to preference forparticular locations or objects. Training and test trials were recordedand scored by video-tracking software (e.g. Noldus Ethovision). Ananimal was scored as exploring an object when its head was orientedtoward the object within a distance of 1-2 cm (rat) or when its nose wastouching the object. Turning around, climbing, or sitting on an objectwas not considered as exploration. If the animal generates a long-termmemory for the familiar object, it will spend significantly more timeexploring the novel object compared to the familiar object during theretention test (Cognitive enhancers are therefore expected to facilitatethis discrimination between the familiar and novel object).

A discrimination index was calculated as previously described(Bourtchouladze et al., Proc. Natl. Acad. Sci. USA 2003, 100,10518-10522). In each experiment, the experimenter was unaware (blind)to the treatment of the subjects during training and testing. Data wereanalyzed by one-way ANOVA with appropriate post-hoc tests using GraphPadPrism or JMP software package.

Results

Exemplary compounds of Formula (I) were found to significantly enhance24 hour memory for NOR in rats. Significant enhancing effects were seenat several concentrations, including 0.1 mg/kg, 1 mg/kg, and 3 mg/kg.

The specification, including the examples, is intended to be exemplaryonly, and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

What is claimed is:
 1. A compound of Formula (I):

or pharmaceutically acceptable salts thereof, wherein X is —O—, and Y is—CH₂— or —CF₂—; or X is CH₂ and Y is CF₂; Z is —CH₂— or —C(═O)—; R¹ is amember selected from the group consisting of: (a) phenyl unsubstitutedor substituted with one, two, three, four, or five R^(a) members; whereeach R^(a) is independently selected from the group consisting of:-halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —CN,—N(C₁₋₆alkyl)₂, —SF₅, —C₃₋₆cycloalkyl, -pyrrolidine, -morpholine,-piperidine, -pyrazole, -furan, -imidazole, -thiophene, -thiazole,-pyridine, and -phenyl, wherein phenyl is unsubstituted or substitutedwith one, two, three, four, or five R^(b) members; where each R^(b) isindependently —Cl or —F; or optionally two adjacent R^(a) members cometogether to form a ring, each optionally unsubstituted or substitutedwith one or more members independently selected from the groupconsisting of: -halo, —C₁₋₆ alkyl, and —C₁₋₆alkoxy; (b) monocyclic orbicyclic heteroaromatic ring each unsubstituted or substituted with one,two, three, or four R^(c) members; where each R^(c) is independentlyselected from the group consisting of: -halo, —C₁₋₆alkyl,—C₁₋₄haloalkyl, —C₁₋₄alkoxy, —N(C₁₋₆alkyl)₂, —(C₁₋₆alkyl)cycloalkyl,-cyclopropyl, -morpholine, -pyrrolidine, -4-chlorophenoxy, and -phenyloptionally unsubstituted or substituted with -halo, —C₁₋₆alkyl, and—C₁₋₄alkoxy; and (c) heterocycloalkyl ring unsubstituted or substitutedwith one or more —F, or —OCH₃; and R² is —C₁₋₆alkyl.
 2. The compound ofclaim 1, wherein Z is —CH₂—.
 3. The compound of claim 1, wherein Z is—C(═O)—.
 4. The compound of claim 1, wherein R² is —CH₃.
 5. The compoundof claim 1, wherein each R^(a) is independently selected from the groupconsisting of: —Cl, —Br, —F, —I, —C₁₋₄alkyl, —C₁₋₄haloalkyl,—C₁₋₄alkoxy, —C₁₋₄haloalkoxy, —CN, —N(CH₃)₂, and -cyclopropyl.
 6. Thecompound of claim 1, wherein each R^(a) is independently selected fromthe group consisting of: -pyrrolidine, -morpholine, -piperidine,-pyrazole, -furan, -imidazole, -thiophene, -thiazole, -pyridine, andphenyl substituted with one or more —Cl, or —F.
 7. The compound of claim1, wherein R¹ is naphthalen-1-yl, naphthalen-2-yl,6-methoxynaphthalen-2-yl, 1-methoxynaphthalen-2-yl,3-methoxynaphthalen-2-yl, 3-methoxynaphthalene-2-yl,6-fluoronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,5,6,7,8-tetrahydronaphthalene-2-yl, 2,3-dihydro-1H-inden-5-yl,2,3-dihydro-1H-inden-5-yl, 2H-1,3-benzodioxol-4-yl,2H-1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,2-difluoro-2H-1,3-benzodioxol-5-yl, 1-ethyl-1H-indole, indole,isoquinoline, 2,3-dihydro-1-benzofuran-5-yl,2,3-dihydro-1-benzofuran-6-yl, 3,4-dihydro-2H-1-benzopyran-6-yl,1-benzofuran, 1-benzofuran-5-yl, 1,3-benzothiazol-6-yl, or1-benzothiophen-5-yl.
 8. The compound of claim 1, wherein R¹ is1-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl, 1-(2-chlorophenyl)-1H-pyrazol-3-yl,1-(2-fluorophenyl)-1H-pyrazol-3-yl, 1-(3-bromophenyl)-1H-pyrazol-3-yl,1-(3-fluorophenyl)-1H-pyrazol-3-yl,1-(4-chlorophenyl)-5-methyl-1H-pyrazol-3-yl,1-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl,1-(4-isopropylphenyl)-5-methyl-1H-pyrazol-3-yl, 1,3-benzothiazole,1,3-dimethyl-1H-pyrazol-5-yl, 1,5-dimethyl-1H-pyrazol-3-yl,1,5-dimethyl-1H-pyrazol-4-yl, 1,6-naphthyridin-2-yl, 1-benzofuran-2-yl,1-benzofuran-3-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl,1-ethyl-1H-pyrazol-5-yl, 1H-indol-3-yl, 1-isopropyl-1H-pyrazol-4-yl,1-methyl-1H-benzo[d]imidazol-2-yl, 1-methyl-1H-indazol-3-yl,1-methyl-1H-indol-2-yl, 1-methyl-1H-indol-3-yl,1-methyl-3-(propan-2-yl)-1H-pyrazole, 1-methyl-3-phenyl-1H-pyrazol-5-yl,1-methyl-5-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-pyrazol-4-yl,1-phenyl-1H-pyrazol-4-yl, 2-(3-fluorophenyl)-1,3-thiazol-5-yl]methyl,2-(3-methoxyphenyl)-1,3-thiazol-5-yl, 2-(4-chlorophenoxy)pyridin-3-yl,2-(4-fluorophenyl)-1,3-thiazol-5-yl,2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl, 2,4-dimethylthiazol-5-yl,2,6-dimethylpyridin-3-yl, 2-bromo-1,3-thiazol-4-yl,2-bromo-1,3-thiazol-5-yl, 2-methoxypyridin-4-yl,2-methyl-1,3-thiazol-5-yl, 2-methyl-2H-indazol-3-yl,2-methyl-6-(trifluoromethyl)pyridin-3-yl,2-methylimidazo[1,2-a]pyridin-3-yl, 2-methylpyridin-3-yl,2-morpholinothiazol-5-yl, 2-phenyl-1,3-thiazol-5-yl,3,5-difluoropyridin-2-yl, 3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl,3,6-dimethylimidazo[2,1-b][1,3]thiazol-5-yl, 3-bromo-1,2-oxazol-5-yl,3-chloropyridin-4-yl, 3-cyclopropylisoxazol-5-yl, 3-fluoropyridin-4-yl,3-isopropyl-1-methyl-1H-pyrazol-5-yl, 3-methylpyridin-2-yl,3-methylpyridin-4-yl, 4-chloropyridin-2-yl, 4-methylpyridin-2-yl,5-bromo-4-methyl-1,3-thiazol-2-yl, 5-bromo-4-methylpyridin-2-yl,5-bromo-6-methylpyridin-2-yl, 5-bromopyridin-2-yl,5-bromopyrimidin-2-yl, 5-chloropyridin-2-yl, 5-chloropyridin-3-yl,5-cyclopropylisoxazol-3-yl, 5-cyclopropylisoxazol-4-yl,5-fluoro-1H-indol-3-yl, 5-fluoropyridin-3-yl, 5-methylpyridin-3-yl,6-methoxypyridin-3-yl, 6-methylpyridin-2-yl, 6-methylpyridin-3-yl,benzo[d]thiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyridin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl,N,N,4-trimethylthiazol-2-amine, N,N-dimethylthiazol-2-amine,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-2-yl, quinolin-3-yl,quinolin-4-yl, or quinoxalin-2-yl.
 9. The compound of claim 1, whereinR¹ is chroman-2-yl, 6-fluorochroman-2-yl, chroman-3-yl,7-methoxychroman-3-yl, 2,3-dihydrobenzofuran-2-yl,(2,3-dihydrobenzo[b][1,4]dioxin-2-yl, or2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, or R¹ is phenyl substitutedwith two or three R^(a) members, where each R¹ is independently -halo,or —C₁₋₆haloalkyl.
 10. The compound of claim 1, wherein Z is —C═O, —R¹is 2,3-dihydro-1-benzofuran, 3,4-dihydro-2H-1-benzopyran, benzofuran,benzothiophene, naphthalene, quinoline, or phenyl, wherein phenyl isunsubstituted or substituted with two, three, or four R^(a) members,where each R¹ is independently selected from the group consisting of:—Cl, —Br, —F, —I, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —OCF₂H, —CN,—N(CH₃)₂, and -cyclopropyl.
 11. The compound of claim 1, wherein Z is—CH₂, —R¹ is phenyl unsubstituted or substituted with two, three or fourR^(a) members, where each R^(a) is independently selected from the groupconsisting of: —Cl, —Br, —F, —I, —C₁₋₄alkyl, —C₁₋₄haloalkyl,—C₁₋₄alkoxy, —CN, —N(CH₃)₂, and -cyclopropyl.
 12. A compound selectedfrom the group consisting of:(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(naphthalen-2-yl)methanone;(2,3-Dihydro-1H-inden-5-yl)(3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methanone;(S)-(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(naphthalen-2-yl)methanone;(3-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(quinolin-4-yl)methanone;(2-(5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)(quinolin-2-yl)methanone;(3,3-Difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)(3-iodo-4-methoxyphenyl)methanone;(3R)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-6-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3-Iodophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine;3,3-Difluoro-1-[(3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(4-Fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-benzoyl-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3-Chloro-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3-Fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-{[4-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(4-Methoxyphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(4-phenylphenyl)carbonyl]morpholine;4-[(4-Chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3-Chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(trifluoromethoxy)phenyl]carbonyl}morpholine;4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]benzonitrile;4-[(3,4-Difluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-2-yl)carbonyl]piperidine;4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]benzonitrile;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(trifluoromethyl)phenyl]carbonyl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[4-(trifluoromethyl)phenyl]carbonyl}morpholine;4-[(3-Ethoxyphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3-Bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(3-Chlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,5-Dichlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile;3,3-Difluoro-1-{[4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(trifluoromethyl)phenyl]carbonyl}piperidine;1-[(3-Chloro-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethyl)phenyl]carbonyl}piperidine;(2R)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine;(2S)-2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine;1-benzoyl-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Difluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-[(3-fluorophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-[(4-fluorophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile;1-[(3-Ethoxyphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(trifluoromethoxy)phenyl]carbonyl}piperidine;(2R)-4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4-[(3-Bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3-Bromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3-Bromo-4-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3-Bromo-5-fluorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3,5-Dibromophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(3-Bromo-5-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,5-Dibromophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(pentafluorosulfanyl)phenyl]carbonyl}piperidine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-{[3-(pentafluorosulfanyl)phenyl]carbonyl}morpholine;1-[(3-Bromo-4-methylphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3-Bromo-4-methylphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(4-Chloropyridin-2-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-Chloro-2-[(3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-(4-Chlorophenoxy)-3-[(3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;4-{[2-Methyl-6-(trifluoromethyl)pyridin-3-yl]carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5R)-1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-[(3-Bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5R)-1-(3-Bromo-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-2-methyl-6-(trifluoromethyl)pyridine;(2S)-4-(3,5-Dibromobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5R)-1-(3,5-Dibromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,5-Dibromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-[3,5-Bis(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,5-Dimethylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Bromo-5-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Bromo-5-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3,5-Dichlorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(4-Bromobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-2,4,5,6-tetrafluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Cyclopropyl-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-[3-Methyl-4-(propan-2-yloxy)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4-Ethoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Bromo-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Chloro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[1-Methyl-3-(propan-2-yl)-1H-pyrazole-5-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[3,5-Dimethyl-4-(propan-2-yloxy)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-[(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;4-[(3-Bromo-5-chlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(3-Bromo-5-chlorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;1-[(4Cyclopropylphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(4Cyclopropylphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[3-Bromo-5-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[3-Bromo-5-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-[3-Bromo-4-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-5-fluoro-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-1-(4-fluoro-3,5-dimethylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Chloro-5-fluoro-4-methoxybenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,4-Difluoro-5-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,5-Dibromo-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(3,4,5-trifluorobenzoyl)piperidine;(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(3,4,5-trichlorobenzoyl)piperidine;(5S)-1-(3,5-Dichloro-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Chloro-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Cyclopropyl-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Cyclopropyl-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Cyclopropyl-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4Cyclopropyl-3-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(4Cyclopropyl-2,3-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4-Bromo-3-chlorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2R)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Chloro-4-cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Chloro-4-cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Fluoro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4-Fluoro-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(3R)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2R)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(3R)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-2-yl)carbonyl]piperidine;1-[(4-Chloro-3-iodophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-[(4-fluoro-3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(1-Benzofuran-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-1-(4-methoxy-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(4-Methoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-(6-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[1-(4-Fluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(6-Fluoronaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;1-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1-benzofuran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline;1-[(3-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3,5-Difluoropyridin-2-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-(3,4-Dichlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;3,3-Difluoro-1-(7-methoxy-3,4-dihydro-2H-1-benzopyran-3-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-(3,4,5-trichlorobenzoyl)morpholine;(2S)-4-(3,5-Dichloro-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(1-Benzofuran-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(1-Methyl-3-phenyl-1H-pyrazole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(2S)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1-benzofuran-6-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2R)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[1-(2-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(2-Chlorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(3-Bromophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(3-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methoxy-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,6-naphthyridine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;3-Methyl-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;1-({Imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;3-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;1-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-Chloro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methoxy-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-({2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)piperidine;3-Chloro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;1-({Imidazo[1,2-a]pyridin-2-yl}carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methyl-1H-pyrrol-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methoxy-5-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,3-Dimethyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-1-yl)carbonyl]piperidine;1-[(3-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-4-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methoxy-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluoro-5-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoxaline;1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indole;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,3-benzothiazole;1-[(3-Methoxy-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Benzofuran-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]piperidine;1-[(3-Cyclopropyl-1,2-oxazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenylphenyl)carbonyl]piperidine;1-[(2,3-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Cyclopropyl-1,2-oxazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methyl-5-phenyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,5-Dimethyl-1H-pyrazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,5-Dimethyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Cyclopropyl-1,2-oxazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine;1-[(2,4-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[1-Methyl-3-(propan-2-yl)-1H-pyrazol-5-yl]carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]piperidine;1-[(4-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dimethoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Ethyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(6-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2H-1,3-Benzodioxol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Methoxynaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(propan-2-yl)phenyl]carbonyl}piperidine;1-[(2,3-Dimethoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Benzothiophen-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,4-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-5-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Benzothiophen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yl)phenyl]carbonyl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,3-benzothiazole;1-[(5-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3-phenylphenyl)carbonyl]piperidine;1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indazole;1-[(1-Benzofuran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indole;1-[(2,5-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluoro-2-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Benzothiophen-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Chloro-5-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,6-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(Dimethyl-1,3-thiazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Fluoro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile;2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-2H-indazole;2-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;1-Benzoyl-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-3-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Methoxy-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-5-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,4-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(Difluoromethyl)phenyl]carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]benzonitrile;1-[(4-Methoxy-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-5-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(4-phenylphenyl)carbonyl]piperidine;1-[(2,6-Dimethylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-6-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-6-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-6-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1-methyl-1H-indole;1-Benzofuran-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(4-methoxy-2-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(5,6,7,8-tetrahydronaphthalene-2-carbonyl)piperidine;3-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1-methyl-1H-indole;1-(1-Benzothiophene-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(3-Chloro-5-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(4-phenylbenzoyl)piperidine;3,3-Difluoro-1-(2-methoxy-4-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-{imidazo[1,2-a]pyridine-6-carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)quinoxaline;3,3-Difluoro-1-{imidazo[1,2-a]pyridine-2-carbonyl}-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(1-Benzothiophene-3-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(2-methoxy-5-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[4-(Difluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(3,4-Dimethoxybenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(5-Chloro-2-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(4-fluoro-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(4-methoxy-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(3-methoxybenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2H-1,3-Benzodioxole-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(3-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[4-(propan-2-yl)benzoyl]piperidine;3,3-Difluoro-1-(2-fluoro-5-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(3-fluoro-5-methoxybenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1H-indene-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(1-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(6-methoxynaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(1-methyl-3-phenyl-1H-pyrazole-5-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-(6-fluoronaphthalene-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-(3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carbonyl)-1,3-benzothiazole;1-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[3-(propan-2-yl)benzoyl]piperidine;3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(1-phenyl-1H-pyrazole-4-carbonyl)piperidine;1-Methyl-2-(2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine-4-carbonyl)-1H-indole;4-(1-Benzofuran-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(1-Benzothiophene-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(3-Chloro-5-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2-Methoxy-4-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-{Imidazo[1,2-a]pyridine-6-carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(1-Benzofuran-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine-4-carbonyl)quinoxaline;4-(1-Benzothiophene-3-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2-Methoxy-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[4-(Difluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(3,4-Dimethoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(5-Chloro-2-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(4-Fluoro-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(4-Methoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(3-Methoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2H-1,3-Benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2-Methoxypyridine-4-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(3-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[4-(propan-2-yl)benzoyl]morpholine;4-(2-Fluoro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(3-Fluoro-5-methoxybenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(1-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(6-Methoxynaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(1-Methyl-3-phenyl-1H-pyrazole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(6-Fluoronaphthalene-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[3-(propan-2-yl)benzoyl]morpholine;3,3-Difluoro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(3,4-Dihydro-2H-1-benzopyran-2-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-(3,4-Dihydro-2H-1-benzopyran-2-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(3,5-Dibromophenyl)(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)methanone-d₄;(3-Bromo-4-fluorophenyl)(3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methanone-d₄;and pharmaceutically acceptable salts thereof.
 13. A compound selectedfrom the group consisting of:3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine;(3R)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine;(3S)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-2-ylmethyl)piperidine;7-(1-(3-Bromobenzyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine;7-(1-((4′-Chloro-3,5-difluoro-[1,1′-biphenyl]-4-yl)methyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine;7-(1-([1,1′-Biphenyl]-4-ylmethyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine;1-{[4-(3-Chlorophenyl)-2,6-difluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(2-Chlorophenyl)-2,6-difluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(4-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(3-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(2-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(2-Chloro-4-fluorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(4-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(3-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(2-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-{3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;1-{[5-(2-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[5-(2-Chloro-4-fluorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{4-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;4-{4-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;1-{[3-(4-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3-(3-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3-(2-Chlorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-{4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;1-{[4-(2-Chloro-4-fluorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[5-(4-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[5-(3-Chlorophenyl)-2-fluorophenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3-(2-Chloro-4-fluorophenyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;7-(1-(2,6-Difluoro-4-(pyridin-3-yl)benzyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine;3-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;4-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;1-[(3,4-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-(naphthalen-1-ylmethyl)piperidine;1-[(4-Chloro-2-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-{4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}morpholine;1-{[4-Fluoro-3-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3-(Furan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(piperidin-1-yl)phenyl]methyl}piperidine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;2-{3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}pyridine;4-{2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]phenyl}morpholine;3-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;2,6-Dimethyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;1-[(2,4-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1H-pyrrol-1-yl)phenyl]methyl}piperidine;1-(1-Benzothiophen-2-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(1-phenyl-1H-pyrazol-4-yl)methyl]piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(pyrrolidin-1-yl)phenyl]methyl}piperidine;1-[(2,5-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(1H-pyrazol-1-yl)phenyl]methyl}piperidine;1-[(4-Chloro-2-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Methoxy-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,4-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2H-1,3-Benzodioxol-4-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,6-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-(1H-Imidazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline;1-[(2-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-2,6-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Dimethoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-6-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(4-methylphenyl)methyl]piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(1H-pyrazol-1-yl)phenyl]methyl}piperidine;1-Benzyl-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Chloro-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yloxy)phenyl]methyl}piperidine;1-[(2-Fluoro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(propan-2-yl)phenyl]methyl}piperidine;1-[(4-Methoxy-2-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Chloro-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole;1-[(3-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-methylphenyl)methyl]piperidine;N,N-Dimethyl-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]aniline;1-[(3,4-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dimethylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluoro-5-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-Methoxy-5-(propan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2H-1,3-Benzodioxol-5-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenylphenyl)methyl]piperidine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole;1-{[4-(Difluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3-methylphenyl)methyl]piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(trifluoromethyl)phenyl]methyl}piperidine;1-[(2-Fluoro-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(1-Benzofuran-2-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethyl)phenyl]methyl}piperidine;1-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-1,3-benzodiazole;5-Fluoro-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenyl-1,3-thiazol-5-yl)methyl]piperidine;1-[(3-Chloro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(1-Benzofuran-3-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Chloro-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dimethylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(1-Benzothiophen-3-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Fluoro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-({3,6-Dimethylimidazo[2,1-b][1,3]thiazol-5-yl}methyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;7-(1-((6-Methoxynaphthalen-2-yl)methyl)piperidin-3-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine;1-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3,5-Dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[1-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]methyl}piperidine;2-Methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;1-{[4-(Furan-2-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[3-(propan-2-yloxy)phenyl]methyl}piperidine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline;1-{[3-(Difluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-(1H-Imidazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;5-Chloro-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;3-Chloro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;1-[(4-Bromo-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3R)-1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;5-bromo-2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;5-Bromo-4-methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;3-Bromo-2-methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;5-Bromo-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyrimidine;1-[(4-Bromo-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3R)-1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(4-Chloro-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1H-inden-5-ylmethyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Bromophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Bromo-2,6-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Bromo-2-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-Ethyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1H-indole;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1,3-thiazol-2-yl)phenyl]methyl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(2-methylpropyl)phenyl]methyl}piperidine;1-[(4-Bromo-3-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4Cyclopropylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Bromo-2-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-tert-Butylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]isoquinoline;1-[(2,3-Difluoro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(trifluoromethoxy)phenyl]methyl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(trifluoromethoxy)phenyl]methyl}piperidine;1-{[2-Methoxy-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]quinoline;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[4-(thiophen-2-yl)phenyl]methyl}piperidine;1-[(3-Fluoro-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chloro-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-Methyl-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[4-Chloro-3-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-3-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dichlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-3-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4-chlorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4-methoxyphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Bromo-3-methylphenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Iodophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3R)-1-[(4-Bromo-3-fluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile;2-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile;1-{[3-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-{[3-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile;1-{[3-Fluoro-5-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Chloro-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-Fluoro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]benzonitrile;(3R)-1-[(4-Chloro-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,5-Difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3R)-1-[(4-Bromo-3,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3,4,5-trifluorophenyl)methyl]piperidine;1-{[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[3-Fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-{[3,5-Difluoro-4-(trifluoromethyl)phenyl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(3,4,5-trifluorophenyl)methyl]piperidine;3-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]pyridine;1-[(2-Bromo-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methyl-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-(4-Fluorophenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-(3-Fluorophenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[2-(3-Methoxyphenyl)-1,3-thiazol-5-yl]methyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-{5-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-yl}morpholine;1-[(2-Bromo-1,3-thiazol-4-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Bromo-1,3-thiazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;N,N-Dimethyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-amine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl]methyl}piperidine;1-[(3-Bromo-1,2-oxazol-5-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Bromo-4,5-difluorophenyl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Bromo-4-methyl-1,3-thiazol-2-yl)methyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;N,N,4-Trimethyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)methyl]-1,3-thiazol-2-amine;and pharmaceutically acceptable salts thereof.
 14. A pharmaceuticalcomposition comprising: a pharmaceutically acceptable excipient; and aneffective amount of at least one at least one compound of claim
 1. 15. Apharmaceutical composition comprising: a pharmaceutically acceptableexcipient; and an effective amount of at least one compound of claim 12.16. A pharmaceutical composition comprising: a pharmaceuticallyacceptable excipient; and an effective amount of at least one compoundof claim
 13. 17. The compound of claim 1, wherein R¹ is phenylunsubstituted or substituted with one, two, three, four, or five R^(a)members.
 18. A compound of Formula (I):

or pharmaceutically acceptable salts thereof, wherein X is —CH₂— or —O—;Y is —CH₂— or —CF₂—; Z is —CH₂— or —C(═O)—; R¹ is a member selected fromthe group consisting of: (a) phenyl unsubstituted or substituted withone, two, three, four, or five R^(a) members; where each R^(a) isindependently selected from the group consisting of: -halo, —C₁₋₆alkyl,—C₁₋₆haloalkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkoxy, —CN, —N(C₁₋₆alkyl)₂, —SF₅,—C₃₋₆cycloalkyl, -pyrrolidine, -morpholine, -piperidine, -pyrazole,-furan, -imidazole, -thiophene, -thiazole, -pyridine, and -phenyl,wherein phenyl is unsubstituted or substituted with one, two, three,four, or five R^(b) members; where each R^(b) is independently —Cl or—F; or optionally two adjacent R^(a) members come together to form aring, each optionally unsubstituted or substituted with one or moremembers independently selected from the group consisting of: -halo,—C₁₋₆ alkyl, and —C₁₋₆alkoxy; (b) bicyclic heteroaromatic ringunsubstituted or substituted with one, two, three, or four R^(c)members; where each R^(c) is independently selected from the groupconsisting of: -halo, —C₁₋₆alkyl, —C₁₋₄haloalkyl, —C₁₋₄alkoxy, —N(C₁₋₆alkyl)₂, —(C₁₋₆ alkyl)cycloalkyl, -cyclopropyl, -morpholine,-pyrrolidine, -4-chlorophenoxy, and -phenyl optionally unsubstituted orsubstituted with -halo, —C₁₋₆alkyl, and —C₁₋₄alkoxy; and (c)heterocycloalkyl ring unsubstituted or substituted with one or more —F,or —OCH₃; and R² is —C₁₋₆alkyl.
 19. The compound of claim 18, wherein R¹is phenyl unsubstituted or substituted with one, two, three, four, orfive R^(a) members.
 20. The compound of claim 18, wherein R¹ is bicyclicheteroaromatic ring unsubstituted or substituted with one, two, three,or four R^(c) members.
 21. The compound of claim 18, wherein R¹ isheterocycloalkyl ring unsubstituted or substituted with one or more —F,or —OCH₃.
 22. The compound of claim 18, wherein R¹ is phenyl substitutedwith one R^(a) member.
 23. The compound of claim 18, wherein R¹ isphenyl substituted with two R^(a) members.
 24. The compound of claim 12,selected from the group consisting of:3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;3-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;6-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]isoquinoline;7-[(2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholin-4-yl)carbonyl]quinoline;1-[(4Cyclopropylphenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(4Cyclopropylphenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[3-Bromo-5-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[3-Bromo-5-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-[3-Bromo-4-(trifluoromethyl)benzoyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-5-fluoro-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-1-(4-fluoro-3,5-dimethylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Chloro-5-fluoro-4-methoxybenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,4-Difluoro-5-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3,5-Dibromo-4-methylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}trifluorobenzoyl)piperidine;(5S)-3,3-Difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}trichlorobenzoyl)piperidine;(5S)-1-(3,5-Dichloro-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Chloro-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(3-Bromo-4,5-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;and pharmaceutically acceptable salts thereof.
 25. The compound of claim12, selected from the group consisting of(2S)-4-(3-Cyclopropyl-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Cyclopropyl-4-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Cyclopropyl-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4Cyclopropyl-3-fluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(4Cyclopropyl-2,3-difluorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4-(4Cyclopropyl-3-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2R)-4-(4Cyclopropyl-2,3-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(4-Bromo-3-chlorobenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2R)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4-Bromo-3-chlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Chloro-4-cyclopropylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(5S)-1-(3-Chloro-4-cyclopropylbenzoyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2S)-4-(3-Fluoro-5-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(4-Fluoro-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(3R)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(3S)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(2R)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(3R)-3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-2-yl)carbonyl]piperidine;1-[(4-Chloro-3-iodophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3,3-Difluoro-1-[(4-fluoro-3-iodophenyl)carbonyl]-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-1-(1-Benzofuran-5-carbonyl)-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;(5S)-3,3-Difluoro-1-(4-methoxy-3-methylbenzoyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;and pharmaceutically acceptable salts thereof.
 26. The compound of claim12, selected from the group consisting of(2S)-4-(4-Methoxy-3-methylbenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-(6-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[1-(4-Fluorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7}piperidine;4-{5-Methyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazole-3-carbonyl}-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7}morpholine;1-[(6-Fluoronaphthalen-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;1-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1-benzofuran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline;1-[(3-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(4-Iodophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[(3,5-Difluoropyridin-2-yl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3,4-Dihydro-2H-1-benzopyran-3-yl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-(3,4-Dichlorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;3,3-Difluoro-1-(7-methoxy-3,4-dihydro-2H-1-benzopyran-3-carbonyl)-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7}piperidine;1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;and pharmaceutically acceptable salts thereof.
 27. The compound of claim12, selected from the group consisting of(2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-(3,4,5-trichlorobenzoyl)morpholine;(2S)-4-(3,5-Dichloro-4-fluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(1-Benzofuran-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(2,2-Difluoro-2H-1,3-benzodioxole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-(1-Methyl-3-phenyl-1H-pyrazole-5-carbonyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;(2S)-4-[(3S)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;1-[(2S)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-(2,3-Dihydro-1-benzofuran-6-carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2R)-2,3-Dihydro-1,4-benzodioxine-2-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;4-[1-(2-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(2-Chlorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(3-Bromophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-[1-(3-Fluorophenyl)-1H-pyrazole-3-carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine;4-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methoxy-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,6-naphthyridine;3-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;3-Methyl-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methyl-6-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;4-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;and pharmaceutically acceptable salts thereof.
 28. The compound of claim12, selected from the group consisting of:3-Methyl-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;1-({Imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;7-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;3-Methyl-2-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;1-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;2-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-Chloro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-Methoxy-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-Fluoro-5-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-({2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)piperidine;3-Chloro-4-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]pyridine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoline;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]isoquinoline;1-({Imidazo[1,2-a]pyridin-2-yl}carbonyl)-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methyl-1H-pyrrol-2-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methoxy-5-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,3-Dimethyl-1H-pyrazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-3-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(naphthalen-1-yl)carbonyl]piperidine;1-[(3-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Fluoro-4-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Methoxy-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(3-Fluoro-5-methoxyphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;and pharmaceutically acceptable salts thereof.
 29. The compound of claim12, selected from the group consisting of:1-[(2-Fluoro-4-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;2-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]quinoxaline;1-Methyl-3-[(3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1H-indole;6-[(3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidin-1-yl)carbonyl]-1,3-benzothiazole;1-[(3-Methoxy-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Benzofuran-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]piperidine;1-[(3-Cyclopropyl-1,2-oxazol-5-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2-Chlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(2-phenylphenyl)carbonyl]piperidine;1-[(2,3-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Cyclopropyl-1,2-oxazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1-Methyl-5-phenyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,5-Dimethyl-1H-pyrazol-4-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(1,5-Dimethyl-1H-pyrazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Difluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Cyclopropyl-1,2-oxazol-3-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine;1-[(2,4-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-{[1-Methyl-3-(propan-2-yl)-1H-pyrazol-5-yl]carbonyl}-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(2,5-Dichlorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;3-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-1-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]piperidine;1-[(4-Chloro-2-fluorophenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;1-[(5-Fluoro-2-methylphenyl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;and pharmaceutically acceptable salts thereof.
 30. A pharmaceuticalcomposition comprising: a pharmaceutically acceptable excipient; and aneffective amount of at least one compound of claim
 24. 31. Apharmaceutical composition comprising: a pharmaceutically acceptableexcipient; and an effective amount of at least one compound of claim 25.32. A pharmaceutical composition comprising: a pharmaceuticallyacceptable excipient; and an effective amount of at least one compoundof claim
 26. 33. A pharmaceutical composition comprising: apharmaceutically acceptable excipient; and an effective amount of atleast one compound of claim
 27. 34. A pharmaceutical compositioncomprising: a pharmaceutically acceptable excipient; and an effectiveamount of at least one compound of claim
 28. 35. A pharmaceuticalcomposition comprising: a pharmaceutically acceptable excipient; and aneffective amount of at least one compound of claim 29.